Benzylpiperizine compound

ABSTRACT

Disclosed is a benzylpiperizine compound represented by formula (1) or a pharmaceutically acceptable salt thereof, which is useful as a medicinal agent such as an antidepressant agent. (In the formula (1), R 1  represents a hydrogen atom or a methyl group; R 2  is a group bound in a p- or m-position relative to a methylene group and represents a chlorine atom bound in a p-position, a bromine atom bound in a p-position, a methyl group bound in a p-position, a chlorine atom bound in a m-position or a bromine atom bound to in a m-position; X represents a methylene or an oxygen atom; and n represents an integer of 1 to 3.)

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional Application of U.S. application Ser.No. 13/527,612, filed Jun. 20, 2012, now allowed, which is aContinuation Application of U.S. application Ser. No. 13/010,194, filedJan. 20, 2011, now U.S. Pat. No. 8,232,405, which is a ContinuationApplication of U.S. application Ser. No. 12/597,942, filed Oct. 28,2009, now U.S. Pat. No. 8,063,223, which is a National Stage ofInternational Application No. PCT/JP2009/051854 filed Feb. 4, 2009,which claims priority from Japanese Patent Application No. 2008-025676filed Feb. 5, 2008, the contents of all of which are incorporated hereinby reference in their entirety.

TECHNICAL FIELD

The present invention relates to a novel benzylpiperidine compound or apharmaceutically acceptable salt thereof, which is useful as a serotoninreuptake inhibitor. More specifically, the benzylpiperidine compound ofthe present invention is a compound having a piperidine parent skeleton,and this compound has a particular substituted benzyl group at4-position of piperidine and further has, at 1-position of piperidine, aphenylethyl (phenethyl) group of which the benzene ring moiety is fusedwith a saturated ring comprising an oxo group. The benzylpiperidinecompound of the present invention has a serotonin reuptake inhibitoryeffect and is therefore useful as, for example, an antidepressant.

BACKGROUND ART

Depression is a chronic disease that affects people of all ages. Ofvarious antidepressants currently used, the most successful one is aselective serotonin reuptake inhibitor (hereinafter, also abbreviated toSSRI). SSRIs have a higher serotonin reuptake inhibitory effect thandopamine and noradrenalin reuptake inhibitory effects. The first drugput on the market as an SSRI was zimelidine. Examples of other SSRIssubsequently launched or under development include fluoxetine,fluvoxamine, citalopram, sertraline, and paroxetine.

Although such SSRIs are widely used as therapeutic drugs for depression,it has been pointed out that they still have some problems. Typicalexamples thereof include the following problems: even SSRIs have aninsufficient therapeutic effect on refractory depression patients, whichoccupy approximately ⅓ of all depression patients; and they require aperiod as long as 3 to 8 weeks for the onset of a sufficientantidepressant effect. Thus, the onset of the antidepressant effects ofSSRIs is slow, whereas their side effects may immediately occur.

Specifically, SSRIs present the problem of a vulnerable period duringwhich patients undergo only the side effects of the drugs withoutobtaining their therapeutic effects. Therefore, treating physiciansoften bear a heavy burden of persuading patients to continuously takethe same drugs even during the period. Furthermore, due to the slowonset of the antidepressant effect, patients at risk of attemptingsuicide restore their initiative before experiencing sufficientimprovements in the symptoms of depression. Therefore, for example, theyare threatened by suicide or needed to be repeatedly hospitalized. Ithas thus been demanded to develop an antidepressant with rapid onset ofthe antidepressant effect.

The reason why SSRIs require a period as long as a few weeks for theonset of an antidepressant effect may be as follows:

SSRIs inhibit acute serotonin reuptake of serotonin turnover. Thisinhibitory effect occurs in the nerve endings of serotonergic neuronsand thereby enhances serotonin-mediated neurotransmission, resulting inthe antidepressant effect. However, this inhibitory effect also occursin cell bodies or dendrites of serotonergic neurons present in raphenuclei and therefore enhances, in the raphe nuclei, serotonin 1Aautoreceptor-mediated suppression (negative feedback reaction) of thespontaneous firing of the serotonergic neurons. As a result,neurotransmission in the serotonergic neurons is less enhanced thanexpected, as a whole, in the initial stage after SSRI administration. Onthe other hand, continuous SSRI administration for a few weeksdesensitizes the serotonin 1A autoreceptor on cell bodies or dendritesof serotonergic neurons in raphe nuclei and thereby eliminates thenegative feedback reaction. As a result, the enhanced activities of theserotonergic neurons in cooperation with serotonin uptake inhibition inthe nerve endings successfully enhance serotonin neurotransmission,resulting in a sufficient antidepressant effect.

Thus, reduction in the period required for the onset of SSRI effects orpotentiation of the antidepressant effect can be achieved by thecombined use with a serotonin 1A receptor antagonist, which blocks theserotonin 1A autoreceptor and thereby eliminates the negative feedbackreaction of serotonin, or by the combined use with a serotonin 1Areceptor agonist, which actively stimulates the serotonin 1Aautoreceptor to reduce a period required for desensitization. Inactuality, it has been reported that the combined use of SSRI withpindolol having high affinity for serotonin 1A receptors potentiates theeffect of the serotonin reuptake inhibitor on depression patients andreduces a period required for the onset of the effect (Arch, Gen.Psychiatry, (1994), 51, 248-251).

When patients take drugs, it is preferred that the drugs be fewer innumber or type. Thus, based on the above findings, a compound having aserotonin reuptake inhibitory effect in combination with affinity forserotonin 1A receptors can probably be used as a novel antidepressant byitself without being combined with other drugs, and this novelantidepressant has a strong antidepressant effect and requires a reducedperiod for the onset of the effect. It has thus been desired to developsuch a compound as a drug.

A previously reported compound having a serotonin reuptake inhibitoryeffect in combination with affinity for serotonin 1A receptors is abenzylpiperidine derivative having a substituted benzyl group at4-position and a substituted phenylethyl group at 1-position (see e.g.,PATENT DOCUMENT 1). Specifically, the document discloses serotoninreuptake inhibitors comprising, as an active ingredient, a cyclic amineor the like represented by the formula (A):

wherein each of plural R⁰ present independently represents a hydrogenatom, a halogen atom, an alkyl group, a substituted alkoxy group, or thelike; R³ represents a hydrogen atom or the like; n represents an integerof 2 or the like; m represents an integer of 2 or the like; R⁵ and R⁶each independently represent a hydrogen atom or the like; and Zrepresents a substituted aryl group or the like.The document further discloses that these serotonin reuptake inhibitorshave serotonin 1A antagonistic activity.

On the other hand, a compound having a substituted benzyl group at4-position of piperidine has been reported in plural documents. Examplesthereof include a document that discloses cyclic amine derivativesacting as therapeutic drugs for cerebral vascular disorders (see PATENTDOCUMENT 2) and a document that discloses 4-substituted piperidinesacting as NMDA receptor antagonists (see PATENT DOCUMENT 3).

Furthermore, a compound having a substituted phenylethyl group at1-position of piperidine has also been reported in several documents.Indole derivatives having a piperidine ring having a cyclic ketonestructure as a substituent on a phenylethyl group have been reported as5-HT1A antagonists (see e.g., PATENT DOCUMENT 4). These indolederivatives have structural difference from the benzylpiperidinecompounds having a substituted benzyl group at 4-position of piperidine.Moreover, it has not been reported that these indole derivatives alsohave a serotonin reuptake inhibitory effect.

None of these patent documents specifically disclose or suggest abenzylpiperidine compound that has a substituted benzyl group at4-position of piperidine and further has, at 1-position of piperidine, aphenylethyl (phenethyl) group of which the benzene ring moiety is fusedwith a saturated ring comprising an oxo group.

Moreover, many antidepressants such as tricyclic antidepressants (TCAs)and SSRIs are known to have a strong inhibitory effect on the enzymeCYP2D6, one of the molecular species of human cytochrome P450, whichparticipates in drug metabolism. On the other hand, it is also knownthat many therapeutic agents for psychiatric disorders that may be usedin combination with TCA or SSRI in the treatment of depression oranxiety symptoms are metabolized by CYP2D6. Thus, in the combined use ofthese drugs, the CYP2D6 inhibitory effect of one of the drugs inhibitsthe metabolism of the other drug. The concentration of the latter drugin blood is increased accordingly, resulting in the possible severe sideeffects. Thus, an antidepressant having a weaker CYP2D6 inhibitoryeffect has a smaller drug interaction with a therapeutic agent forpsychiatric disorders metabolized by CYP2D6 in the combined use.Therefore, such an antidepressant can be expected to serve as a highlysafe drug. It has thus been demanded to develop the drug.

Furthermore, CYP2D6 is known to vary largely in enzyme activity amongindividuals due to genetic polymorphisms. Drugs metabolized at highrates by CYP2D6 vary largely in in-vivo drug concentration amongindividuals. Their drug concentrations in blood are highly possiblyincreased more largely in a poor metabolizer (PM) than in an extensivemetabolizer (EM). Moreover, such drugs possibly exhibit a stronger druginteraction with a drug that inhibits CYP2D6 or is metabolized byCYP2D6. Thus, a lower rate of CYP2D6 contribution to drug metabolismoffers a smaller pharmacokinetic influence by the genetic polymorphismsof CYP2D6. Therefore, such a drug can be expected to be highly safe. Ithas also been demanded to develop the drug.

-   PATENT DOCUMENT 1: U.S. Pat. No. 6,787,560-   PATENT DOCUMENT 2: WO88/02365-   PATENT DOCUMENT 3: WO97/23216-   PATENT DOCUMENT 4: WO2005/108389

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a novel serotoninreuptake inhibitor also having affinity for serotonin 1A receptors. Sucha serotonin reuptake inhibitor is expected to serve as a therapeuticdrug for, for example, depression or anxiety (anxiety disorder). Thus,an object of the present invention is to provide a more highly safe drugexcellent in therapeutic effect. Specifically, an object of the presentinvention is to provide a drug that has an improved human serotoninreuptake inhibitory activity in combination with affinity for serotonin1A receptors, has a weaker inhibitory effect on CYP2D6, one of themolecular species of human cytochrome P450, and undergoes small CYP2D6contribution to drug metabolism in humans.

Means for Solving the Problems

The present inventors have conducted diligent studies to attain theobject and consequently found that a benzylpiperidine compound or apharmaceutically acceptable salt thereof characterized in terms of achemical structure by having a di-substituted benzyl group having a2-methoxyethoxy or 2-hydroxyethoxy group at 3-position of the benzenering moiety and having, at 1-position of piperidine, a phenylethyl groupof which the benzene ring moiety is fused with a saturated ringcomprising an oxo group, not only has a high human serotonin reuptakeinhibitory effect in combination with binding affinity for human 5-HT1Areceptors, but also has weaker CYP2D6 inhibition and undergoes smallCYP2D6 contribution to metabolism. Based on these findings, the presentinvention has been completed.

The present invention relates to a benzylpiperidine compound or apharmaceutically acceptable salt thereof represented by the following[1] to [8], which is useful as a serotonin reuptake inhibitor.Specifically, the present invention relates to:

[1] a compound represented by the formula (1) or a pharmaceuticallyacceptable salt thereof:

wherein R¹ represents a hydrogen atom or a methyl group; R² represents agroup bonded at a p- or m-position in relation to a methylene groupbonded to the piperidine ring, specifically, a chlorine atom bonded atthe p-position, a bromine atom bonded at the p-position, a methyl groupbonded at the p-position, a chlorine atom bonded at the m-position, or abromine atom bonded at the m-position; X represents a methylene group oran oxygen atom; and n represents an integer of 1 to 3;[2] the compound according to [1] or a pharmaceutically acceptable saltthereof, wherein X represents a methylene group and n represents aninteger of 1 or 2, or wherein X represents an oxygen atom and nrepresents an integer of 2 or 3;[3] the compound according to [1] or [2] or a pharmaceuticallyacceptable salt thereof, wherein R¹ represents a methyl group;[4] the compound according to any of [1] to [3] or a pharmaceuticallyacceptable salt thereof, wherein R² represents a bromine atom bonded atthe p-position;[5] the compound according to any of [1] to [4] or a pharmaceuticallyacceptable salt thereof, wherein X represents an oxygen atom and nrepresents the integer 2;[6] the compound according to [1] or [2] or a pharmaceuticallyacceptable salt thereof, wherein R² represents a bromine atom bonded atthe p-position; X represents an oxygen atom; and n represents theinteger 2;[7] the compound according to [1] or a pharmaceutically acceptable saltthereof, wherein the compound represented by the formula (1) is selectedfrom the group consisting of the following compounds (01) to (15):

-   (01)    6-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one,-   (02)    7-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one,-   (03)    6-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (04)    7-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydro-1-benzoxepin-5(2H)-one,-   (05)    6-(2-{4-[4-Chloro-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (06)    6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one,-   (07)    7-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one,-   (08)    6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (09)    7-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydro-1-benzoxepin-5(2H)-one,-   (10)    6-(2-{4-[3-(2-Methoxyethoxy)-4-methylbenzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (11)    6-(2-{4-[3-Chloro-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (12)    6-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one,-   (13)    7-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one,-   (14)    6-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,    and-   (15)    7-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydro-1-benzoxepin-5(2H)-one;    and    [8] A pharmaceutically acceptable salt of a compound according to    any of [1] to [7], wherein the pharmaceutically acceptable salt is    hydrochloride, hydrobromide, fumarate, benzenesulfonate, or    succinate.

Moreover, the present invention relates to a pharmaceutical compositionor a therapeutic or preventive drug represented by the following [9] to[12]. Specifically, the present invention relates to:

[9] a pharmaceutical composition comprising a compound according to anyof [1] to [7] or a pharmaceutically acceptable salt thereof as an activeingredient;[10] a serotonin reuptake inhibitor comprising a compound according toany of [1] to [7] or a pharmaceutically acceptable salt thereof as anactive ingredient;[11] an antidepressant or an anxiolytic drug comprising a compoundaccording to any of [1] to [7] or a pharmaceutically acceptable saltthereof as an active ingredient; and[12] an antidepressant comprising a compound according to any of [1] to[7] or a pharmaceutically acceptable salt thereof as an activeingredient.

Moreover, the present invention relates to an intermediate representedby the following [13] of the benzylpiperidine compound of the presentinvention according to any of [1] to [7]. Specifically, the presentinvention relates to:

[13] a compound represented by the formula (11):

wherein R¹ represents a hydrogen atom or a methyl group; and R²represents a group bonded at a p- or m-position in relation to amethylene group bonded to the piperidine ring, specifically, a chlorineatom bonded at the p-position, a bromine atom bonded at the p-position,a methyl group bonded at the p-position, a chlorine atom bonded at them-position, or a bromine atom bonded at the m-position.

Moreover, the present invention relates to an intermediate representedby the following [14] of the benzylpiperidine compound of the presentinvention according to any of [1] to [7]. Specifically, the presentinvention relates to:

[14] a compound represented by the formula (12):

wherein X represents a methylene group or an oxygen atom; n representsan integer of 1 to 3; and LG¹ represents an iodine atom, a bromine atom,a chlorine atom, or a substituted sulfonyloxy group.

Advantages of the Invention

The present invention can provide a benzylpiperidine compound or apharmaceutically acceptable salt thereof, which is useful as a serotoninreuptake inhibitor that can be used as a therapeutic drug for depressionor the like. Specifically, the present invention can provide abenzylpiperidine compound or a pharmaceutically acceptable salt thereof,which has a high human serotonin reuptake inhibitory activity incombination with binding affinity for human 5-HT1A receptors, has weakerCYP2D6 inhibition, and undergoes small CYP2D6 contribution tometabolism.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically.

A benzylpiperidine compound of the present invention represented by theformula (1) is characterized in terms of a chemical structure by havinga di-substituted benzyl group having a 2-methoxyethoxy or2-hydroxyethoxy group at 3-position of the benzene ring moiety andhaving, at 1-position of piperidine, a phenylethyl group of which thebenzene ring moiety is fused with a saturated ring comprising an oxogroup.

In the present invention, the term “substituted sulfonyloxy group” meansa sulfonyloxy group substituted by an alkyl group or an optionallysubstituted phenyl group. In this context, examples of the alkyl groupinclude linear or branched alkyl groups having 1 to 6 carbon atoms andspecifically include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, and trifluoromethyl groups.Examples of the substituent for the optionally substituted phenyl groupinclude halogen atoms (in this context, examples of the halogen atomsinclude fluorine, chlorine, bromine, and iodine atoms), alkyl groups (inthis context, the alkyl groups refer to linear or branched alkyl groupshaving 1 to 6 carbon atoms, and examples thereof specifically includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, and hexyl groups), a trifluoromethyl group, a cyanogroup, a nitro group, and alkoxy groups (in this context, the alkoxygroups refer to linear or branched alkoxy groups having 1 to 6 carbonatoms, and examples thereof specifically include methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, and hexyloxy groups). Preferable examples of the substitutedsulfonyloxy group include methanesulfonyloxy, benzenesulfonyloxy, andp-toluenesulfonyloxy groups. More preferable examples of the substitutedsulfonyloxy group include benzenesulfonyloxy and p-toluenesulfonyloxygroups.

In the formula (1), preferable examples of R¹ include a methyl group.

In the formula (1), R² represents a group bonded at a p- or m-positionin relation to a methylene group bonded to the piperidine ring,specifically, a chlorine atom bonded at the p-position, a bromine atombonded at the p-position, a methyl group bonded at the p-position, achlorine atom bonded at the m-position, or a bromine atom bonded at them-position. For example, when R² represents a chlorine atom bonded atthe p-position, a bromine atom bonded at the p-position, or a methylgroup bonded at the p-position, the compound of the formula (1)represents a compound represented by the formula (1-p):

wherein R¹, X, and n are as defined above; and R^(2p) represents achlorine atom, a bromine atom, or a methyl group.

On the other hand, when R² represents a chlorine atom bonded at them-position or a bromine atom bonded at the m-position, the compound ofthe formula (1) represents a compound represented by the formula (1-m):

wherein R¹, X, and n are as defined above; and R^(2m) represents achlorine atom or a bromine atom.

In the formula (1), preferable examples of R² include a bromine atombonded at the p-position. Specifically, a compound represented by theformula (1-p-Br) is preferable:

wherein R¹, X, and n are as defined above.

The compound of the formula (1) wherein X represents a methylene groupand n represents the integer 1 represents a compound represented by theformula (1-C-1):

wherein R¹ and R² are as defined above.

The compound of the formula (1) wherein X represents a methylene groupand n represents the integer 2 represents a compound represented by theformula (1-C-2):

wherein R¹ and R² are as defined above.

The compound of the formula (1) wherein X represents a methylene groupand n represents the integer 3 represents a compound represented by theformula (1-C-3):

wherein R¹ and R² are as defined above.

The compound of the formula (1) wherein X represents an oxygen atom andn represents the integer 1 represents a compound represented by theformula (1-O-1):

wherein R¹ and R² are as defined above.

The compound of the formula (1) wherein X represents an oxygen atom andn represents the integer 2 represents a compound represented by theformula (1-O-2):

wherein R¹ and R² are as defined above.

The compound of the formula (1) wherein X represents an oxygen atom andn represents the integer 3 represents a compound represented by theformula (1-O-3):

wherein R¹ and R² are as defined above.

In the formula (1), the combination of X and n is preferably acombination wherein X represents methylene and n represents an integerof 1 or 2, or wherein X represents an oxygen atom and n represents aninteger of 2 or 3. Specifically, the compound represented by the formula(1-C-1), (1-C-2), (1-O-2), or (1-O-3) is preferable. More preferableexamples of the combination of X and n include a combination wherein Xrepresents an oxygen atom and n represents the integer 2. Specifically,the compound represented by the formula (1-O-2) is more preferable.

More specifically, the following compounds (01) to (15) are preferable:

-   (01)    6-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one,-   (02)    7-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one,-   (03)    6-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (04)    7-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydro-1-benzoxepin-5(2H)-one,-   (05)    6-(2-{4-[4-Chloro-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (06)    6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one,-   (07)    7-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one,-   (08)    6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (09)    7-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydro-1-benzoxepin-5(2H)-one,-   (10)    6-(2-{4-[3-(2-Methoxyethoxy)-4-methylbenzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (11)    6-(2-{4-[3-Chloro-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,-   (12)    6-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one,-   (13)    7-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one,-   (14)    6-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one,    and-   (15)    7-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydro-1-benzoxepin-5(2H)-one.

The benzylpiperidine compound of the present invention can be producedfrom compounds known in the art according to methods shown in ProductionMethods 1 to 5 below, similar methods thereto, or appropriatecombinations of synthetic methods well known by those skilled in theart. Some of starting compounds (11), (12), (13), (15), (18), and (19)are novel compounds, which can however be produced according to methodsdescribed later in Examples, similar methods thereto, or appropriatecombinations of synthetic methods well known by those skilled in theart.

Moreover, in the present specification, the following abbreviations maybe used for simplifying the description:

Boc: tert-butoxycarbonyl group,

Piv: tert-butylcarbonyl group,

Me: methyl group,

Et: ethyl group,

Ph: phenyl group,

Bn: benzyl group,

Ms: methanesulfonyl group,

Bs: benzenesulfonyl group,

Ts: p-toluenesulfonyl group,

p: para (e.g., the abbreviation “p-Br” means a bromine atom bonded at apara-position),

m: meta (e.g., the abbreviation “m-Br” means a bromine atom bonded at ameta-position), and

DMSO: dimethyl sulfoxide.

Production Method 1: Production Method for Compound (1)

The compound represented by the formula (1) or a salt thereof can beproduced, for example, by the following method:

herein R¹, R², X, n and LG¹ are as defined above.

The compound (1) of interest or the salt thereof can be obtained byreacting a compound (11) or a salt thereof with a compound (12). Thereaction can be carried out in an appropriate inert solvent for 10minutes to 48 hours in a temperature range of approximately −20° C. tothe boiling point of the solvent used, if necessary in the presence of abase and if necessary in the presence of a phase transfer catalyst.

Examples of the base include: organic bases such as triethylamine,diisopropylethylamine, and pyridine; inorganic bases such as potassiumcarbonate, sodium carbonate, cesium carbonate, potassium bicarbonate,sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogenphosphate, potassium phosphate, sodium dihydrogen phosphate, disodiumhydrogen phosphate, sodium phosphate, potassium hydroxide, sodiumhydroxide, and sodium hydride; and metal alkoxides such as sodiummethoxide and potassium tert-butoxide. Preferable examples thereofinclude potassium carbonate and dipotassium hydrogen phosphate.

Examples of the phase transfer catalyst include tetrabutylammoniumhydrogen sulfate.

Examples of the inert solvent include: halogenated hydrocarbons such aschloroform and dichloromethane; aromatic hydrocarbons such as benzeneand toluene; ether solvents such as diethyl ether, tetrahydrofuran(THF), and 1,4-dioxane; lower alcohols such as methanol, ethanol, and2-propanol; aprotic polar solvents such as acetonitrile, acetone, methylethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethylsulfoxide; and mixed solvents thereof. More preferable examples of thesolvent include acetonitrile, toluene, dimethylformamide, andN-methyl-2-pyrrolidinone, and mixed solvents thereof.

The leaving group LG¹ is preferably a bromine or substituted sulfonyloxygroup, more preferably a benzenesulfonyloxy or p-toluenesulfonyloxygroup.

Production Method 2: Production Method for Compound (11)

The compound (11) or the salt thereof used as a starting material inProduction Method 1 can be produced, for example, by the followingmethod with reference to a document such as U.S. Pat. No. 6,787,560:

wherein R¹ and R² are as defined above; PG¹ represents a protectinggroup for the nitrogen atom; and LG² represents a leaving group, whereinexamples of the protecting group PG¹ for the nitrogen atom includealkyloxycarbonyl groups such as t-butyloxycarbonyl and9-fluorenylmethyloxycarbonyl groups, and examples of the leaving groupLG² include halogen atoms such as chlorine, bromine, and iodine atomsand substituted sulfonyloxy groups such as p-toluenesulfonyloxy andmethanesulfonyloxy groups.

A compound (13) is converted to a phosphonic acid ester (14a) or aphosphonium salt (14b). This conversion to the phosphonic acid ester(14a) can be carried out by reacting triethyl phosphite in the absenceof a solvent or in an inert solvent for 1 hour to 3 days at atemperature between an ice-cold temperature and the boiling point of thesolvent used or triethyl phosphite. Alternatively, the conversion to thephosphonium salt (14b) can be carried out by reacting triphenylphosphinein an inert solvent for 1 hour to 3 days at a temperature between anice-cold temperature and the boiling point of the solvent used.

This phosphonic acid ester (14a) or phosphonium salt (14b) can beconverted to a compound (16) through reaction with ketone (15) in thepresence of a base in an appropriate inert solvent for 10 minutes to 48hours at a temperature of approximately −20° C. to the boiling point ofthe solvent used.

Examples of the base include: organic bases such as triethylamine andpyridine; inorganic bases such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and sodium hydride; and metalalkoxides such as sodium methoxide and potassium tert-butoxide.

Examples of the inert solvent include: halogenated hydrocarbons such aschloroform and dichloromethane; aromatic hydrocarbons such as benzeneand toluene; ether solvents such as diethyl ether, tetrahydrofuran,1,4-dioxane, and 1,2-dimethoxyethane; lower alcohols such as methanol,ethanol, and 2-propanol; aprotic polar solvents such as acetonitrile,dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; andmixed solvents thereof.

The compound (16) can be converted to a compound (17) through catalytichydrogenation. This hydrogenation for the compound wherein R² representsa bromine atom bonded at the p-position or a bromine atom bonded at them-position can be carried out by reacting the compound at 0° C. to 50°C. in an appropriate inert solvent at an ambient or pressurized hydrogenatmosphere over a catalyst such as rhodium catalysts (e.g., rhodiumcarbon), platinum catalysts (e.g., platinum carbon and platinum oxide),ruthenium catalysts (e.g., ruthenium carbon), and palladium chloride.Examples of the appropriate inert solvent include: ethyl acetate;aromatic hydrocarbons such as benzene and toluene; ether solvents suchas diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane;lower alcohols such as methanol, ethanol, and 2-propanol; aprotic polarsolvents such as dimethylformamide, N-methyl-2-pyrrolidinone, anddimethyl sulfoxide; and mixed solvents thereof. More preferable examplesof the catalyst include rhodium carbon and platinum carbon. Moreover, inthis case, more preferable examples of the solvent include ethylacetate.

The compound (17) can be deprotected by a conventional method to obtainthe compound (11) of interest. When the protecting group is at-butyloxycarbonyl group, the deprotection is carried out by treatingthe compound (17) with an inorganic acid (e.g., hydrochloric acid orsulfuric acid) or an organic acid (e.g., trifluoroacetic acid) in anappropriate inert solvent at a temperature between −20° C. and theboiling point of the solvent used. Examples of the inert solventinclude: halogenated hydrocarbons such as chloroform anddichloromethane; aromatic hydrocarbons such as benzene and toluene;ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and1,2-dimethoxyethane; lower alcohols such as methanol, ethanol, and2-propanol; aprotic polar solvents such as acetonitrile,dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; andmixed solvents thereof. When the protecting group is a9-fluorenylmethyloxycarbonyl group, the deprotection is carried out bytreating the compound (17) with an organic base (e.g., pyrrolidine,piperidine, morpholine, triethylamine, or diisopropylethylamine) in anappropriate inert solvent at a temperature between −20° C. and theboiling point of the solvent used. Examples of the inert solventinclude: halogenated hydrocarbons such as chloroform anddichloromethane; aromatic hydrocarbons such as benzene and toluene;ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and1,2-dimethoxyethane; lower alcohols such as methanol, ethanol, and2-propanol; aprotic polar solvents such as acetonitrile,dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; andmixed solvents thereof.

Production Method 3: Production Method for Compound (12)

The compound (12) used as a starting material in Production Method 1 canbe produced, for example, by the following method:

wherein X and n are as defined above; and R³ represents a hydrogen atomor an alkyl group, wherein examples of the alkyl group include linear orbranched alkyl groups having 1 to 6 carbon atoms and can specificallyinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl,and hexyl groups.

A compound (18) can be reacted with an appropriate reducing agent (e.g.,lithium aluminum hydride, lithium borohydride, sodium borohydride, ordiborane) for 10 minutes to 48 hours in an appropriate inert solvent(e.g., ether solvents such as diethyl ether, tetrahydrofuran (THF), and1,4-dioxane) at a temperature between −20° C. and the boiling point ofthe solvent used to obtain a compound (19).

The compound (19) can be oxidized with an oxidizing agent (e.g.,manganese dioxide) in an appropriate inert solvent to obtain a compound(20). Examples of the appropriate inert solvent include halogenatedsolvents such as chloroform and dichloromethane; ether solvents such asacetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, and1,2-dimethoxyethane; aprotic polar solvents such as acetonitrile,dimethylformamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide; andmixed solvents thereof.

The hydroxyl group of the compound (20) can be converted by aconventional method to a halogen atom (e.g., a chlorine, bromine, oriodine atom) or a substituted sulfonyloxy group (e.g., ap-toluenesulfonyloxy, benzenesulfonyloxy, or methanesulfonyloxy group)to obtain the compound (12). Specifically, the compound (12) can beobtained by reacting the compound (20) with, for example,methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonylchloride for 10 minutes to 48 hours in the presence of a base in aninert solvent at a temperature between −20° C. and the boiling point ofthe solvent used. Examples of the appropriate inert solvent include:halogenated solvents such as chloroform and dichloromethane; ethersolvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and1,2-dimethoxyethane; aprotic polar solvents such as acetonitrile,dimethylformamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide; andmixed solvents thereof. Examples of the appropriate base include:organic bases such as triethylamine and pyridine; and inorganic basessuch as potassium carbonate and sodium hydroxide. Moreover, the compound(12) wherein LG¹ is halogen (e.g., a chlorine or bromine atom) can beobtained by reacting the compound (12) wherein LG¹ is a substitutedsulfonyloxy group (e.g., a p-toluenesulfonyloxy or methanesulfonyloxygroup) with, for example, lithium bromide for 10 minutes to 48 hours inan inert solvent at a temperature between −20° C. and the boiling pointof the solvent used. Examples of the appropriate inert solvent include:halogenated solvents such as chloroform and dichloromethane; ethersolvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and1,2-dimethoxyethane; aprotic polar solvents such as acetonitrile,dimethylformamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide; andmixed solvents thereof. Moreover, in an alternative method, the compound(12) can be obtained, for example, by reacting the compound (20) withcarbon tetrachloride or carbon tetrabromide in the presence oftriphenylphosphine in an appropriate inert solvent.

Production Method 4: Production Method for Compound (12)

The starting compound (12) can also be produced, for example, by thefollowing method:

wherein X, n, and LG¹ are as defined above.

The primary hydroxyl group of the compound (19) can be converted by aconventional method to a substituted sulfonyloxy group (e.g., ap-toluenesulfonyloxy, benzenesulfonyloxy, or methanesulfonyloxy group)to obtain a compound (21). The hydroxyl group of the compound (21) canbe oxidized by a conventional method, for example, oxidation withmanganese dioxide or dimethyl sulfoxide (DMSO), in an appropriate inertsolvent to obtain the compound (12).

Production Method 5: Production Method for Compound (20)

The intermediate compound (20) in Production Method 3 can be produced,for example, by the following method:

wherein R³, X, and n are as defined above; and PG² represents a methoxygroup, a methylthio group, or the like, or two PG² may together form aring and represent a cyclic acetal group such as a 1,3-dioxolane or1,3-dioxane group.

The ketone of the compound (18) is converted by a conventional method todialkyl acetal or dialkyl thioacetal to obtain a compound (22). Thiscompound is reduced with an appropriate reducing agent (e.g., lithiumaluminum hydride, lithium borohydride, sodium borohydride, or diborane)in an appropriate inert solvent to obtain a compound (23). The compound(23) can be deprotected by an appropriate method to obtain the compound(20).

The compound (18) can be synthesized according to a method described in,for example, Journal of Medicinal Chemistry (1994), 37 (21), 3482.,Journal of Medicinal Chemistry (1979), 22 (12), 1464., FR Patent No.2672601, or JP-A-61-236774.

The starting materials and the reagents used in the production methodsare commercially available compounds or can be produced from compoundsknown in the art using methods known in the art, unless otherwisespecified. Moreover, functional groups in the compound of the formula(1) may be converted appropriately to obtain another compound of theformula (1). The conversion of functional groups can be carried outaccording to general methods usually carried out [see e.g., R. C.Larock, Comprehensive Organic Transformations, (1989)].

In the production methods, when any functional group located at a siteother than the reaction point is altered under the described reactionconditions or is inappropriate for the described methods, thisfunctional group can be protected with an appropriate protecting groupprior to the reaction and then deprotected to obtain the compound ofinterest. For example, usual protecting groups as described in, forexample, T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons Inc., (1981) can be used as the protecting group.Specifically, examples of the protecting group can include: for amines,ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzoyl,and benzyl; for hydroxyl groups, trialkylsilyl, acetyl, benzoyl, andbenzyl; and for ketones, dimethyl acetal, 1,3-dioxane, 1,3-dioxolane,S,S′-dimethyl dithioacetal, 1,3-dithiane, and oxime.

The introduction and deprotection of the protecting group can be carriedout according to methods routinely used in synthetic organic chemistry(see e.g., Protective Groups in Organic Synthesis) or methods equivalentthereto.

The intermediates and the compounds of interest in the productionmethods can be isolated and purified by purification methods routinelyused in synthetic organic chemistry, for example, neutralization,filtration, extraction, washing, drying, concentration,recrystallization, and various chromatography techniques. Moreover, theintermediates may be subjected to the subsequent reactions without beingparticularly purified.

Some of the compounds of the present invention represented by theformula (1) may include tautomers. Examples of the tautomerism includeevents represented by the formula (24):

The present invention encompasses all possible isomers including thetautomers, and mixtures thereof.

The pharmaceutically acceptable salt of the compound represented by theformula (1) is a nontoxic salt routinely used. Examples thereof include:acid addition salts such as organic acid salts (e.g., acetate,propionate, trifluoroacetate, maleate, fumarate, citrate, succinate,tartrate, methanesulfonate, benzenesulfonate, formate, andtoluenesulfonate) and inorganic acid salts (e.g., hydrochloride,hydrobromide, hydroiodide, sulfate, nitrate, and phosphate); salts withamino acids (e.g., arginine acid, aspartic acid, and glutamic acid);metal salts such as alkali metal salts (e.g., sodium salts and potassiumsalts) and alkaline-earth metal salts (e.g., calcium salts and magnesiumsalts); ammonium salts; and organic base salts such as trimethylaminesalts, triethylamine salts, pyridine salts, picoline salts,dicyclohexylamine salts, and N,N′-dibenzylethylenediamine salts.

The pharmaceutically acceptable salt of the compound represented by theformula (1) can be obtained only by directly purifying the compound (1)obtained in the form of a pharmaceutically acceptable salt or bydissolving or suspending the compound (1) obtained in a free from in anappropriate organic solvent and forming a salt by a usual method by theaddition of an acid or a base to this solution or suspension. Forexample, the compound (1) can be mixed with a pharmaceuticallyacceptable acid or alkali in a solvent such as water, methanol, ethanol,or acetone to form a salt.

Moreover, the compound represented by the formula (1) and thepharmaceutically acceptable salt thereof may be present in the form ofhydrates with water or solvates with various solvents such as ethanol.These hydrates and solvates are also encompassed in the presentinvention.

The obtained crystals of the compound represented by the formula (1) andthe pharmaceutically acceptable salt thereof may include crystalpolymorphs. These crystal polymorphs are also encompassed in the presentinvention.

The benzylpiperidine compound of the present invention and thepharmaceutically acceptable salt thereof have a human serotonin reuptakeinhibitory effect. Hence, the compound and the salt are useful astherapeutic drugs for diseases mediated by the serotonergic nervoussystem. Examples of the diseases mediated by the serotonergic nervoussystem include depression and anxiety. The depression is included inmood disorders in psychiatric disorder classification. The mooddisorders are mainly classified into depressive disorders and bipolardisorders. More specifically, examples of the general depression include(i) depressive disorders including major depressive disorder, dysthymicdisorder, and depressive disorders not otherwise specified, (ii)depression, and (iii) seasonal affective disorder. The compound and thesalt are useful as therapeutic drugs for these diseases or as preventivedrugs for relapse thereof. Furthermore, the compound and the salt arealso useful as therapeutic drugs for (iv) major depressive episodes inbipolar disorders or as preventive drugs for relapse thereof. On theother hand, the anxiety (anxiety disorder) mainly includes anxietydisorders and phobias. Examples of the anxiety (anxiety disorder) forwhich the compound and the salt are useful as therapeutic drugs or aspreventive drugs for relapse include (v) panic disorder, obsessivecompulsive disorder, posttraumatic stress disorder, acute stressdisorder, generalized anxiety disorder, and anxiety disorders attributedto general physical diseases, (vi) anxiety disorders includingsubstance-induced anxiety disorder, (vii) agoraphobia, (viii) socialphobia, (ix) avoidant personality disorder, and (x) psychosomaticdisease. Moreover, the compound and the salt are also useful fordepression or anxiety symptoms caused by other diseases (schizophrenia,dementia, etc.). Furthermore, the compound and the salt are also usefulfor treating or preventing diseases such as: memory disorders includingdementia, forgetfulness, and memory disorders associated with aging;eating disorders including anorexia nervosa and bulimia nervosa;obesity; somnipathy; schizophrenia; alcoholism, smoking addiction,nicotine dependence, and drug (narcotic, stimulant drug, psychotropic,etc.) dependence; cluster headache; migraine; pains; Alzheimer'sdisease; chronic paroxysmal migraine; headache associated withangiopathy; Parkinson's disease including dementia, depression, andanxiety caused by Parkinson's disease, neuroleptic-induced Parkinsonism,and tardive dyskinesia; endocrine abnormality such ashyperprolactinemia; vasospasm (particularly, of the cerebrovascularsystem); hypertension; kinetic gastrointestinal troubles andgastrointestinal troubles involving a secretion change; and sexualdysfunction including premature ejaculation.

The dose of the benzylpiperidine compound of the present invention orthe pharmaceutically acceptable salt thereof differs depending on theage and conditions of a patient. The compound (1) is effective ataverage one dose of approximately 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg,250 mg, 500 mg, or 1000 mg for the diseases such as depression andanxiety. In general, it can be administered to a human at a dose of 0.1mg/individual to approximately 1,000 mg/individual, preferably 1mg/individual to approximately 100 mg/individual, per day.Administration is performed once or several times daily. For example, 1,2, or 3 dose(s) are given each time.

The benzylpiperidine compound of the present invention or thepharmaceutically acceptable salt thereof can be administered orally orparenterally (e.g., intravenously, subcutaneously, intramuscularly,intrathecally, locally, rectally, transdermally, nasally, orpulmonarily) as a pharmaceutical composition used in treatment. Examplesof dosage forms for oral administration include dosage forms such astablets, capsules, pills, granules, fine granules, powders, solutions,syrups, and suspensions. Examples of dosage forms for parenteraladministration include preparations in forms such as aqueous injections,non aqueous injections, suppositories, nasal preparations, andtransdermal preparations [lotions, emulsion, ointments, creams, jellies,gels, and adhesive skin patches (e.g., tapes, transdermal patchpreparations, and poultices), powders for external use, etc.]. Thesepreparations can be prepared using techniques conventionally known inthe art and contain a nontoxic and inert carrier or excipient usuallyused in the pharmaceutical field.

Substances that are routinely used in the pharmaceutical field and areunreactive with the compound represented by the formula (1) or thepharmaceutically acceptable salt thereof are used as pharmaceuticalcarriers. Specifically, the pharmaceutical composition comprising thecompound represented by the formula (1) or the pharmaceuticallyacceptable salt thereof can contain a pharmaceutical carrier such asexcipients, binders, lubricants, stabilizers, disintegrants, buffers,solubilizing agents, tonicity agents, solubilizing agents, pH adjusters,surfactants, emulsifying agents, suspending agents, dispersants,suspension stabilizers, thickeners, viscosity modifiers, gelling agents,soothing agents, preservatives, plasticizers, transdermal absorptionpromoters, antioxidants, humectants, antiseptics, and flavors. Two ormore of these pharmaceutical carrier additives may be selectedappropriately for use.

Specific examples of the pharmaceutical carrier additives includelactose, inositol, glucose, sucrose, fructose, mannitol (mannite),dextran, sorbitol (sorbit), cyclodextrin, starch (potato starch, cornstarch, amylopectin, etc.), partially pregelatinized starch, saccharose,magnesium aluminometasilicate, synthetic aluminum silicate, sodiumalginate, crystalline cellulose, sodium carboxymethylcellulose,hydroxypropyl starch, calcium carboxymethylcellulose, ion-exchangedresins, methylcellulose, gelatin, gum arabic, pullulan,hydroxypropylcellulose, low-substituted hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose,hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin,alginic acid, sodium alginate, light anhydrous silicic acid, magnesiumstearate, calcium stearate, aluminum stearate, cetostearyl alcohol, wax,paraffin, talc, tragacanth, bentonite, veegum, carboxyvinyl polymers,titanium dioxide, fatty acid esters, sorbitan fatty acid esters, sodiumlauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin,glycerogelatin, polysorbates, macrogol, squalane, silicone oil,vegetable oils (sesame oil, olive oil, soybean oil, cottonseed oil,castor oil, etc.), liquid paraffin, soft paraffin, white petroleum,yellow petroleum, paraffin, wool fat, waxes (beeswax, carnauba wax,white beeswax, etc.), water, propylene glycol, polyethylene glycol,glycerol, lauryl alcohol, myristyl alcohol, oleyl alcohol, cetylalcohol, ethanol, sodium chloride, sodium hydroxide, hydrochloric acid,citric acid, lauric acid, myristic acid, stearic acid, oleic acid,benzyl alcohol, glutamic acid, glycine, methyl p-hydroxybenzoate, propylp-hydroxybenzoate, p-hydroxybenzoic acid esters, cholesterol esters,ethylene glycol monoalkyl esters, propylene glycol monoalkyl esters,glycerin monostearate, sorbitan fatty acid esters, isopropyl myristate,isopropyl palmitate, carboxypolymethylene, saccharin, strawberry flavor,peppermint flavor, cacao butter, polyisobutylene, vinyl acetatecopolymers, acrylic copolymers, triethyl citrate, acetyl triethylcitrate, diethyl phthalate, diethyl sebacate, dibutyl sebacate,acetylated monoglyceride, diethylene glycol, dodecylpyrrolidone, urea,ethyl laurate, azone, kaolin, bentonite, zinc oxide, agarose,carrageenan, gum acacia, xanthan gum, potassium laurate, potassiumpalmitate, potassium myristate, sodium cetyl sulfate, sulfated castoroil (turkey-red oil), Span (sorbitan stearate, sorbitan monooleate,sorbitan sesquioleate, sorbitan trioleate, etc.), Tween (polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80,polysorbate 85, polyoxyethylene sorbitan fatty acid ester, etc.),polyoxyethylene hydrogenated castor oil (so-called HCO), polyoxyethylenelauryl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether,polyethylene glycol monolaurate, polyethylene glycol monostearate,poloxamers (so-called Pluronics), lecithin (also including purifiedphospholipids isolated from lecithin, such as phosphatidylcholine andphosphatidylserine), and hydrogenated lecithin.

The benzylpiperidine compound of the present invention and thepharmaceutically acceptable salt thereof, when used in thepharmaceutical applications as described above, are usually administeredin the form of preparations comprising the compound or the salt mixedwith pharmaceutical carriers, and these preparations are preparedaccording to usual methods. For example, the pharmaceutical compositioncan comprise 0.051 to 99% by weight, preferably 0.05 to 80% by weight,more preferably 0.1 to 70% by weight, even more preferably 0.1 to 50% byweight of the benzylpiperidine compound of the present invention or thepharmaceutically acceptable salt thereof as an active ingredient. Thesepreparations may also contain other therapeutically valuableingredients.

The benzylpiperidine compound of the present invention or thepharmaceutically acceptable salt thereof can be used in combination witha drug (combined drug) such as antidepressants, anxiolytic drugs,therapeutic drugs for schizophrenia, dopamine receptor agonists,therapeutic drug for Parkinson's disease, antiepileptics,anticonvulsants, analgesics, hormone preparations, therapeutic drugs formigraine, adrenaline β receptor antagonists, therapeutic drugs fordementia, and therapeutic drugs for mood disorder, for the purpose ofpotentiating its effect. Moreover, it can be used in combination with adrug (combined drug) such as antiemetics, sleep inducing drugs, andanticonvulsants, for the purpose of suppressing its side effects. Thetiming of administration of the compound of the present invention andthe combined drug is not limited. They may be administeredsimultaneously or at any interval to an administration target. Moreover,the compound of the present invention and the combined drug may beadministered as a mixture. The dose of the combined drug can be selectedappropriately with respect to doses clinically used. Moreover, the ratiobetween the compound of the present invention and the combined drugformulated can be selected appropriately according to an administrationtarget, an administration route, a target disease, symptoms,combinations, and so on. For example, when the administration target isa human, 0.01 to 1000 parts by weight of the combined drug can be usedwith respect to 1 part by weight of the compound of the presentinvention.

Hereinafter, the present invention will be described more specificallywith reference to Reference Examples, Examples, and Test Examples.However, the technical scope of the present invention is not intended tobe limited to these Examples. In this context, not all compound namesshown in Reference Examples and Examples below follow the IUPACnomenclature.

The compounds were identified using proton nuclear magnetic resonanceabsorption spectra (¹H-NMR spectra) or the like. For some of thecompounds, their ¹H-NMR spectrum data and melting points are shown.Moreover, purity or the like was also confirmed by liquid chromatographyanalysis. This analysis was conducted using a column SUMIPAX ODS C-212(5 μm, 6 mmφ×15 cm) at a measurement wavelength set to 220 nm and amobile phase flow rate set to 1.0 ml/min. The mobile phase used was amixed solvent of 0.05% trifluoroacetic acid-acetonitrile (solution A)and 0.05% trifluoroacetic acid-water (solution B). Condition 1 involvedincreasing the proportion of the solution A in 0.625% increments per 1minute such that the mixing ratio between the solutions A and B(solution A:solution B) was set to 25:75 at the start of measurement (0min) and 50:50 after 40 minutes into the measurement. Condition 2involved allowing the mixing ratio between the solutions A and B toremain constant at 40:60. For some of the compounds, the retention timesat which the compounds were detected and the mixing ratio between thesolutions A and B (Condition 1 or 2) are also shown.

Reference Example 1 4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidinehydrochloride, compound (RE1)

The compound was synthesized according to the following ProductionMethod 1 or 2:

Production Method 1

Compound (1-1-1): 1,3-Dibromo-5-(2-methoxyethoxy)benzene

2-Bromoethyl methyl ether (31.2 g, 224 mmol) was added at roomtemperature to a solution of 3,5-dibromophenol (37.7 g, 150 mmol) andpotassium carbonate (41.4 g, 300 mmol) in dimethylformamide (150 mmol),and the reaction mixture was stirred at 80° C. for 9 hours. The mixturewas cooled to room temperature and then separated into aqueous andorganic layers by the addition of water (300 mL), toluene (150 mL), andethyl acetate (150 mL). The aqueous layer was extracted with a mixedsolution of toluene (50 mL) and ethyl acetate (50 mL). The combinedorganic layers were washed with water (50×2 mL) and brine (50 mL) anddried over anhydrous sodium sulfate, and the solvent was then distilledoff under reduced pressure. The obtained concentrated residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=20:1→15:1) to obtain the title compound (1-1-1) (44.3 g, 95%) asa brown oil.

Compound (1-1-2): 3-Bromo-5-(2-methoxyethoxy)benzaldehyde

n-Butylmagnesium chloride (0.89 M solution in tetrahydrofuran, 116 mL,100 mmol) was added dropwise over 25 minutes to a solution ofn-butyllithium (1.6 M solution in n-hexane, 126 mL, 198 mmol) in toluene(120 mL) with the solution temperature kept at 3 to 5° C. by cooling inan ice bath, and the reaction mixture was stirred at this temperaturefor 30 minutes. A solution of the compound (1-1-1) (46.1 g, 149 mmol) intoluene (420 mL) was added dropwise thereto over 1 hour with thesolution temperature kept at 0 to 3° C., and the reaction mixture wasstirred for 2 hours. Then, N,N-dimethylformamide (28.7 mL, 373 mmol) wasadded dropwise thereto at the solution temperature of 4 to 5° C. over 40minutes, and the reaction mixture was stirred for 2 hours. A 2 N aqueoushydrochloric acid solution (300 mL) was added thereto, and the mixturewas warmed to room temperature and separated into aqueous and organiclayers. The aqueous layer was subjected to extraction with toluene (100mL). The combined organic layers were washed with water and brine andthen dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The obtained concentrated residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=10:1→7:1) to obtain the title compound (1-1-2) (28.8 g, 74%).

Compound (1-1-3): [3-Bromo-5-(2-methoxyethoxy)phenyl]methanol

Sodium borohydride (4.22 g, 112 mmol) was added in small portions atroom temperature to a solution of the compound (1-1-2) (28.9 g, 112mmol) in methanol (112 mL) with water cooling, and the reaction mixturewas stirred at room temperature for 3 hours. Water (200 mL) was addedthereto, and the methanol was distilled off under reduced pressure,followed by extraction with ethyl acetate (200 mL+50 mL). The organiclayer was washed with brine and dried over anhydrous sodium sulfate, andthe solvent was then distilled off under reduced pressure to obtain thetitle compound (1-1-3) (28.7 g, 98%) as a pale yellow oil.

Compound (1-1-4): 3-Bromo-5-(2-methoxyethoxy)benzyl methanesulfonate

A solution of methanesulfonyl chloride (16.0 g, 140 mmol) in toluene (15mL) was added dropwise over 50 minutes to a solution of the compound(1-1-3) (24.3 g, 93.1 mmol), trimethylamine hydrochloride (890 mg, 9.3mmol), and triethylamine (25.9 mL, 186 mmol) in toluene (186 mL) withthe solution temperature kept at 10° C. or lower in a salt-ice bath, andthe reaction mixture was stirred at the solution temperature of 5° C. orlower for 1 hour. 2-Diethylaminoethylamine (5.95 g, 51.2 mmol) was addedthereto at the solution temperature of 5° C. or lower, and the mixturewas stirred for 20 minutes. Subsequently, a 5% aqueous potassiumbisulfate solution (250 mL) and water (100 mL) were added to thereaction solution, and the mixture was warmed to room temperature andseparated into aqueous and organic layers. The organic layer was washedwith water, and the toluene was then distilled off under reducedpressure to obtain the title compound (1-1-4) (33.1 g).

Compound (1-1-5): 1-Bromo-3-(bromomethyl)-5-(2-methoxyethoxy)benzene

Lithium bromide monohydrate (30.7 g, 293 mmol) was added at roomtemperature to a solution of the compound (1-1-4) (33.1 g, whichcorresponds to 97.6 mmol) in anhydrous tetrahydrofuran (195 mL), and thereaction mixture was heated under reflux for 1 hour. The mixture wascooled to room temperature and then separated into aqueous and organiclayers by the addition of toluene (180 mL) and water. The aqueous layerwas extracted with toluene (50 mL). The combined organic layers werewashed with brine and dried over anhydrous sodium sulfate, and thetoluene was then distilled off under reduced pressure to obtain thetitle compound (1-1-5) (29.3 g, 93%).

Compound (1-1-6):[3-Bromo-5-(2-methoxyethoxy)benzyl](triphenyl)phosphonium bromide

A solution of the compound (1-1-5) (31.8 g, 98 mmol) andtriphenylphosphine (28.3 g, 108 mmol) in toluene (98 mL) was heatedunder reflux for 3 hours. The reaction mixture was gradually cooled toroom temperature, and the resulting precipitate was collected byfiltration, washed with toluene (40 mL), and dried under reducedpressure to obtain the title compound (1-1-6) (50.1 g, 87%).

Compound (1-1-7): tert-Butyl4-{[3-bromo-5-(2-methoxyethoxy)phenyl]methylidene}piperidine-1-carboxylate

A suspension of the compound (1-1-6) (50.1 g, 85 mmol),1-tert-butoxycarbonyl-4-piperidone (17.4 g, 87 mmol), and potassiumcarbonate (23.6 g, 171 mmol) in 2-propanol (250 mL) was stirred at 40°C. for 4 hours, at 50° C. for 2 hours, at 60° C. for 3.5 hours, and thenheated under reflux at 80° C. for 7.5 hours. The reaction mixture wascooled to room temperature, and the salt was then filtered off. Thefiltrate was concentrated under reduced pressure. The obtainedconcentrated residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=10:1→7:1) to obtain the title compound (1-1-7)(34.6 g, 95%) as a colorless oil.

Compound (1-1-8): tert-Butyl4-[3-bromo-5-(2-methoxyethoxy)benzyl]piperidine-1-carboxylate

The compound (1-1-7) (34.6 g, 81 mmol) was subjected to atmospherichydrogenation reaction at room temperature for 26 hours in ethyl acetate(80 mL) over 5% rhodium carbon (9.74 g). The catalyst was filtered off.The filtrate was concentrated under reduced pressure to obtain the titlecompound (1-1-8) (34.2 g, 98%).

Compound (RE1):

A 10% hydrochloric acid-methanol solution (103 mL) was added at roomtemperature to a solution of the compound (1-1-8) (34.2 g, 80 mmol) inmethanol (34 mL), and the reaction mixture was stirred at roomtemperature for 1 day. The solvent was distilled off under reducedpressure. Then, diethyl ether was added to the obtained concentratedresidue, and the resulting precipitate was collected by filtration,washed with diethyl ether and then dried under reduced pressure toobtain a white solid (27.5 g). To this white solid, acetonitrile (132mL) was added, and the mixture was heated to 50° C. The completedissolution thereof was confirmed, and the solution was then graduallycooled and stirred at 40° C. for 30 minutes. Then, the solution wascooled to 0° C. over 1 hour and stirred at 0° C. for 1 hour. Theprecipitate was collected by filtration, then washed with coldacetonitrile (20 mL), and dried under reduced pressure to obtain thecompound (RE1) of interest (22.6 g, 85%) as a white powder.

Retention time (Condition 1): 15.56 minutes

Melting point: 107-108° C.

¹H-NMR (400 MHz, d⁶-DMSO) δ: 1.25-1.40 (2H, m), 1.67 (2H, d like, J=14Hz), 1.72-1.85 (1H, m), 2.49 (2H, d, J=6.8 Hz), 2.77 (2H, dt, J=2.4, 12Hz), 3.20 (2H, br d, J=12.6 Hz), 3.34 (3H, s), 3.63 (2H, t like, J=4.5Hz), 4.09 (2H, t like, J=4.5 Hz), 6.80 (1H, t, J=1.7 Hz), 6.96-6.99 (2H,m).

Production Method 2

Compound (1-2-1): Diethyl (3-Bromo-5-methoxybenzyl)phosphonate

5,5-Dimethyl-1,3-dibromohydantoin (13.1 g, 46 mmol) andazobisisobutyronitrile (1.50 g, 9.1 mmol) were simultaneously added at80° C. to a solution of 1-bromo-3-methoxy-5-methylbenzene (17.0 g, 91mmol) synthesized by a method of the document (J. Med. Chem. 2001, 44,1866) in monochlorobenzene (500 mL), and the reaction mixture wasstirred at 80° C. for 30 minutes. The reaction solution was cooled toroom temperature and then poured into a 10% aqueous sodium thiosulfatesolution (100 mL), and the mixture was stirred for 30 minutes. Themixture was separated into aqueous and organic layers. The aqueous layerwas subjected to extraction with toluene (100 mL). The combined organiclayers were dried over anhydrous sodium sulfate, and the solvent wasthen distilled off under reduced pressure to obtain1-bromo-3-(bromomethyl)-5-methoxybenzene. Without further purification,this compound was dissolved in triethyl phosphite (14.3 mL, 97 mmol) andtoluene (50 mL), and the reaction mixture was heated under reflux for 7hours. After cooling to room temperature, the solvent was distilled offunder reduced pressure. The obtained concentrated residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:2) toobtain the title compound (1-2-1) (20.8 g, 64%).

Compound (1-2-2): tert-Butyl4-(3-bromo-5-methoxybenzylidene)piperidine-1-carboxylate

A solution of the compound (1-2-1) (19.0 g, 56 mmol) in anhydroustetrahydrofuran (100 mL) was added dropwise at 50° C. over 15 minutes toa suspension of sodium hydride (60% suspension, 2.71 g, 68 mmol) inanhydrous tetrahydrofuran (100 mL). The reaction mixture was stirred at50° C. for 25 minutes. Then, a solution of1-tert-butoxycarbonyl-4-piperidone (14.5 g, 73 mmol) in anhydroustetrahydrofuran (100 mL) was added dropwise thereto at 50° C. over 30minutes, and the reaction mixture was stirred for 1 hour. Subsequently,1-tert-butoxycarbonyl-4-piperidone (5.00 g, 25 mmol) and sodium hydride(60% suspension, 1.00 g, 25 mmol) were added thereto, and the reactionmixture was stirred for 1.5 hours. After cooling to room temperature,water (100 mL) was added thereto, and the mixture was subjected toextraction with ethyl acetate. The organic layer was washed with brineand then dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure. Then, n-hexane (10 mL) and ethylacetate (10 mL) were added to the obtained concentrated residue, and theresulting solid was collected by filtration, washed with n-hexane/ethylacetate (1:1, 5 mL×3), and dried under reduced pressure to obtain thetitle compound (1-2-2) (11.3 g, 52%).

Compound (1-2-3): (tert-Butyl4-(3-bromo-5-methoxybenzyl)piperidine-1-carboxylate

The compound (1-2-2) (19.0 g, 50 mmol) was subjected to atmospherichydrogenation reaction at room temperature for 1.5 hours in ethylacetate (300 mL) over 5% rhodium carbon (10.3 g, 10 mol %). The catalystwas filtered off. The filtrate was concentrated under reduced pressureto obtain the title compound (1-2-3) (20.6 g, quantitative).

Compound (1-2-4): 4-(3-Bromo-5-methoxybenzyl)piperidine hydrochloride

A 10% hydrochloric acid-methanol solution (150 mL) was added at roomtemperature to a solution of the compound (1-2-3) (20.6 g, 50 mmol) inmethanol (30 mL), and the reaction mixture was stirred at 50° C. for 45minutes. After cooling to room temperature, the solvent was distilledoff under reduced pressure. Then, diethyl ether was added to theobtained concentrated residue, and the resulting precipitate wascollected by filtration, washed with diethyl ether and then dried underreduced pressure to obtain the title compound (1-2-4) (15.4 g, 97%).

Retention time (Condition 1): 16.40 minutes

Compound (1-2-5): tert-Butyl4-(3-bromo-5-hydroxybenzyl)piperidine-1-carboxylate

A solution of the compound (1-2-4) (15.0 g, 47 mmol) in dichloromethane(200 mL) was cooled in an ice bath, and a 1 M borontribromide-dichloromethane solution (70 mL, 70 mmol) was added dropwisethereto over 30 minutes. The reaction mixture was stirred for 2 hourswith ice cooling, and a 1 M boron tribromide-dichloromethane solution(50 mL, 50 mmol) was further added dropwise thereto with ice cooling.The reaction mixture was stirred for 2 hours, and methanol (50 mL) wasthen added dropwise thereto with the solution temperature kept at 20° C.or lower. The solvent was distilled off under reduced pressure. Theobtained concentrated residue was dissolved by the addition of a 2 Naqueous sodium hydroxide solution (200 mL) and 1,4-dioxane (400 mL), anda solution of di-tert-butyl dicarbonate (10.3 g, 47 mmol) in 1,4-dioxane(50 mL) was added dropwise thereto at room temperature over 30 minutes.The reaction mixture was stirred overnight at room temperature. Then,the 1,4-dioxane was distilled off under reduced pressure, and water (300mL) was added to the concentrated residue, followed by extraction withethyl acetate. The organic layer was washed with brine and dried overanhydrous magnesium sulfate, and the solvent was then distilled offunder reduced pressure. The obtained concentrated residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=4:1) toobtain the title compound (1-2-5) (15.8 g, 91%).

Compound (1-1-8):

A solution of the compound (1-2-5) (15.8 g, 43 mmol), 2-bromoethylmethyl ether (6.0 mL, 64 mmol), potassium iodide (7.09 g, 43 mmol), andpotassium carbonate (11.8 g, 85 mmol) in dimethylformamide (100 mL) wasstirred at 60 to 70° C. for 8 hours. 2-Bromoethyl methyl ether (1.0 mL,11 mmol) was further added thereto, and the reaction mixture was stirredfor 2 hours. The mixture was cooled to room temperature and then pouredto water (500 mL), followed by extraction with ethyl acetate/toluene(1:1, 200 mL×3). The organic layer was washed with water, and thesolvent was then distilled off under reduced pressure. The obtainedconcentrated residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=5:1) to obtain the title compound (1-1-8) (18.4g, quantitative).

Compound (RE1):

A 10% hydrochloric acid-methanol solution (200 mL) was added at roomtemperature to a solution of the compound (1-1-8) (18.4 g, 43 mmol) inmethanol (30 mL), and the reaction mixture was stirred overnight at roomtemperature. The methanol was distilled off under reduced pressure.Diethyl ether (100 mL) was added to the obtained concentrated residue,and the resulting precipitate was collected by filtration, washed withdiethyl ether (50 mL) and then dried under reduced pressure to obtainthe compound (RE1) of interest (14.7 g, 95%).

Reference Example 2 4-[3-Chloro-5-(2-methoxyethoxy)benzyl]piperidine,compound (RE2)

A solution of the compound (1-1-8) (800 mg, 1.8 mmol) and copper(I)chloride (537 mg, 5.4 mmol) in dimethylformamide (5.4 mL) was stirred at150° C. for 6 hours. After cooling to room temperature, the salt wasfiltered off. The solvent in the filtrate was distilled off underreduced pressure. A 2 N aqueous sodium hydroxide solution and chloroformwere added to the obtained concentrated residue, and the resultingprecipitate was filtered off. The filtrate was subjected to extractionwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was then distilled off under reduced pressureto obtain the title compound (RE2) (520 mg, quantitative).

¹H-NMR (300 MHz, CDCl₃) δ: 1.04-1.20 (2H, m), 1.52-1.83 (3H, m), 2.45(2H, bd, J=6.8 Hz), 2.47-2.61 (2H, m), 3.04 (2H, bd, J=11.9 Hz), 3.45(3H, s), 3.72-3.75 (2H, m), 4.07-4.10 (2H, m), 6.62 (1H, bt, J=1.8 Hz),6.72-6.78 (2H, m).

Reference Example 3 4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidinehydrochloride, Compound (RE3)

The compound was synthesized according to the following ProductionMethod 1, 2, or 3:

Production Method 1

Compound (3-1-1): 4-Bromo-3-(2-methoxyethoxy)benzoic acid

Potassium t-butoxide (24.29 g, 217 mmol) was added at room temperatureto a solution of 2-methoxyethanol (16.48 g, 217 mmol) in anhydrousN-methyl-2-pyrrolidinone (175 mL) under nitrogen atmosphere. Thedissolution thereof was visually confirmed, and 4-bromo-3-fluorobenzoicacid (19.00 g, 86.8 mmol) was then added thereto in small portions. Thereaction mixture was stirred at 90° C. for 6 hours. The mixture wascooled to room temperature and then added dropwise to a solution ofconcentrated hydrochloric acid (36%, 25 mL) and water (500 mL) over 40minutes with water cooling. The mixture was stirred at the solutiontemperature of 20 to 25° C. for 1 hour, and the resulting precipitatewas then collected by filtration, washed with water (20 mL×2) andacetonitrile (20 mL×2), and dried under reduced pressure to obtain awhite solid (26.41 g). This white solid was added to acetonitrile (380mL), and the mixture was heated to around a reflux temperature. Thedissolution thereof was visually confirmed, and the solution was thencooled to around 75° C. at which crystal deposition started. Then, themixture was stirred for 1 hour with the temperature kept at 65 to 70° C.Then, the mixture was cooled again to around 30° C. over 2.5 hours andsubsequently stirred for 1 hour with the solution temperature kept at20° C. by water cooling. The resulting precipitate was collected byfiltration, washed with acetonitrile (20 mL×2) to obtain the titlecompound (3-1-1) (20.09 g, 85%) as a light brown needle-like crystal.

Compound (3-1-2): [4-Bromo-3-(2-methoxyethoxy)phenyl]methanol

A boron trifluoride/diethyl ether complex (35 mL, 285 mmol) was addeddropwise to a suspension of sodium borohydride (8.08 g, 213.5 mmol) inanhydrous tetrahydrofuran (100 mL) with water cooling, and the mixturewas stirred at this temperature for 1 hour. A solution of the compound(3-1-1) (19.50 g, 71.2 mmol) in anhydrous tetrahydrofuran (300 mL) wasadded dropwise thereto over 30 minutes with the solution temperaturekept at 25° C. or lower by water cooling. The reaction mixture wasstirred for 3 hours, and water (200 mL) was then added dropwise theretoover 20 minutes with the solution temperature kept at 20° C. or lower byice cooling. The mixture was separated into aqueous and organic layersby the addition of toluene (200 mL). The aqueous layer was extractedwith toluene (200 mL). The combined organic layers were washed with a 3%aqueous sodium bicarbonate solution (200 mL) and water (200 mL), and thetoluene was then distilled off under reduced pressure. Toluene (200 mL)was added to the concentrated residue, and the toluene was distilled offunder reduced pressure to obtain the title compound (3-1-2) (18.18 g).

Compound (3-1-3): 4-Bromo-3-(2-methoxyethoxy)benzyl methanesulfonate

A toluene (18 mL) solution of methanesulfonyl chloride (8.56 g, 74.7mmol) was added dropwise over 30 minutes to a solution of the compound(3-1-2) (18.00 g, which corresponds to 71.17 mmol), trimethylaminehydrochloride (467 mg, 7.12 mmol), and triethylamine (19.8 mL, 142 mmol)in toluene (90 mL) with the solution temperature kept at 5° C. or lowerin a salt-ice bath, and the reaction mixture was stirred at the solutiontemperature of 5° C. or lower for 2 hours. The reaction solution waspoured into a 5% aqueous potassium bisulfate solution (180 mL) with thetemperature kept at 10° C. or lower by cooling in an ice bath, and themixture was stirred for 30 minutes. The mixture was warmed to roomtemperature and separated into aqueous and organic layers. The aqueouslayer was extracted with toluene (90 mL). The combined organic layerswere washed with water (180 mL), and the toluene was distilled off underreduced pressure to obtain the title compound (3-1-3) (22.43 g).

Compound (3-1-4): 1-Bromo-4-(bromomethyl)-2-(2-methoxyethoxy)benzene

Anhydrous lithium bromide (18.54 g, 214 mmol) was added at roomtemperature to a solution of the compound (3-1-3) (22.43 g, whichcorresponds to 71.17 mmol) in anhydrous tetrahydrofuran (100 mL), andthe reaction mixture was heated under reflux for 1 hour. The mixture wascooled to room temperature and then separated into aqueous and organiclayers by the addition of water (100 mL) and toluene (100 mL). Theaqueous layer was extracted with toluene (100 mL). The combined organiclayers were washed with a 5% aqueous sodium bicarbonate solution (100mL) and water (100 mL) in this order, and the toluene was distilled offunder reduced pressure to obtain the title compound (3-1-4) (19.54 g) asa white solid.

Alternatively, the present title compound (3-1-4) can also besynthesized directly from the compound (3-1-2) as follows without beingsubjected to the intermediary step with the compound (3-1-3):

A solution of the compound (3-1-2) (16.0 g, 61.3 mmol) in toluene (80 g)and aqueous hydrogen bromide (47%, 53 g) was stirred at the solutiontemperature of 65 to 70° C. for 2 hours. The mixture was cooled to roomtemperature and then separated into aqueous and organic layers by theaddition of water (16 g). The organic layer was washed with a 5% aqueoussodium bicarbonate solution (48 g) and water (48 g) in this order. Theorganic layer was concentrated under reduced pressure to obtain thetitle compound (3-1-4) (17.9 g, 90%).

Compound (3-1-5):[4-Bromo-3-(2-methoxyethoxy)benzyl](triphenyl)phosphonium bromide

Triphenylphosphine (18.67 g, 71.17 mmol) was added to a solution of thecompound (3-1-4) (19.54 g, which corresponds to 71.17 mmol) in toluene(100 mL), and the reaction mixture was heated under reflux for 3.5hours. The mixture was cooled to room temperature and then stirred for 1hour with the temperature kept at 20° C. with water cooling, and theresulting precipitate was then collected by filtration, washed withtoluene (40 mL×3), and dried under reduced pressure to obtain the titlecompound (3-1-5) (32.44 g, 78%).

Compound (3-1-6): tert-Butyl4-[4-bromo-3-(2-methoxyethoxy)benzylidene]piperidine-1-carboxylate

A solution of the compound (3-1-5) (32.00 g, 54.6 mmol),1-tert-Butoxycarbonyl-4-piperidone (11.42 g, 57.3 mmol), and potassiumcarbonate (11.30 g, 81.9 mmol) in 2-propanol (160 mL) was heated underreflux for hours. After cooling to room temperature, the salt wasseparated by filtration, and this residue salt was washed with2-propanol (30 mL×2). The filtrate was concentrated under reducedpressure to obtain a concentrated residue (41.08 g). Toluene was addedthereto and distilled off under reduced pressure (200 mL×2).Subsequently, toluene (96 mL) was added to the concentrated residue, andn-hexane (290 mL) was added dropwise thereto over 30 minutes with thetemperature kept at 20 to 25° C. by water cooling. The mixture wasstirred at this temperature for 1 hour and then stirred for 1 hour withice cooling, and the resulting precipitate was separated by filtration.The residue on the filter was washed with toluene/n-hexane(toluene:n-hexane=1:3, 20 mL×2). The solvent in the filtrate wasdistilled off under reduced pressure to obtain the title compound(3-1-6) (27.93 g) as a pale yellow oil.

Compound (3-1-7): tert-Butyl4-[4-bromo-3-(2-methoxyethoxy)benzyl]piperidine-1-carboxylate

The compound (3-1-6) (27.93 g, which corresponds to 54.6 mmol) wassubjected to atmospheric hydrogenation reaction at the solutiontemperature of 15 to 20° C. for 3 hours in ethyl acetate (232 mL) over5% rhodium carbon (5.80 g). The catalyst was filtered off throughcelite. Then, the ethyl acetate was distilled off under reduced pressureto obtain the title compound (3-1-7) (25.73 g) as a white solid.

Compound (RE3):

A solution of the compound (3-1-7) (25.73 g, which corresponds to 54.6mmol) in 2-propanol (115 mL) was warmed to the solution temperature of55 to 60° C. Concentrated hydrochloric acid (36%, 23.2 mL) was addeddropwise thereto over 5 minutes, and the reaction mixture was stirred atthe solution temperature of 55 to 60° C. for 4 hours. After cooling toroom temperature, the 2-propanol was distilled off under reducedpressure to obtain a concentrated residue (42.91 g). This concentratedresidue was separated into aqueous and organic layers by the addition ofwater (115 mL) and toluene (115 mL). The organic layer was extractedwith water (50 mL). The combined aqueous layers were adjusted toapproximately pH 10 with sodium hydroxide and subjected to extractionwith toluene (200+100+100 mL). The organic layer was washed with water(50 mL), and the toluene was distilled off under reduced pressure toobtain a concentrated residue (18.57 g). This concentrated residue wasdissolved in 2-propanol. To the solution, concentrated hydrochloric acid(36%, 5.58 g, 54.6 mmol) was added at room temperature, and the2-propanol was distilled off under reduced pressure. 2-Propanol (200mL×2) was added to the concentrated residue and distilled off underreduced pressure to obtain a concentrated residue (18.61 g) as a whitepowder. To this concentrated residue, 2-propanol (115 mL) was added. Theuniform solution at the solution temperature around 65 to 70° C. wasvisually confirmed and then allowed to cool slowly. Crystal depositionat around 60° C. was confirmed, and n-hexane (60 mL) was then addeddropwise thereto at the solution temperature of 55 to 60° C. over 20minutes. The suspension was stirred at the solution temperature of 55 to60° C. for 1 hour and then allowed to cool slowly again to the solutiontemperature of 30° C. or lower. Then, the suspension was stirred for 1hour with the solution temperature kept at 15 to 20° C. by water coolingand further stirred at the solution temperature of 5° C. or lower for 1hour by ice cooling. The precipitate was collected by filtration, washedwith a cold n-hexane (23 mL)-2-propanol (12 mL) mixed solution and thendried under reduced pressure to obtain the compound (RE3) of interest(17.30 g) as a white powder.

Retention time (Condition 1): 15.55 minutes

Melting point: 171-172° C.

¹H-NMR (300 MHz, CDCl₃) δ: 1.47-1.94 (5H, m), 2.55 (2H, d, J=5.5 Hz),2.79 (2H, t like, J=12 Hz), 3.47 (2H, d like, J=13 Hz), 3.51 (3H, s),3.81 (2H, t, J=4.8 Hz), 4.15 (2H, t, J=4.8 Hz), 6.62 (1H, dd, J=7.9, 1.8Hz), 6.68 (1H, d, J=1.7 Hz), 7.43 (1H, d, J=8.1 Hz), 9.50 (2H, br s).

Production Method 2

Compound (3-2-1): Methyl 3-(2-methoxyethoxy)-4-nitrobenzoate

A solution of Methyl 3-hydroxy-4-nitrobenzoate (15.0 g, 76 mmol),2-bromoethyl methyl ether (14.5 g, 99 mmol), potassium iodide (12.6 g,76 mmol), and potassium carbonate (21.4 g, 155 mmol) indimethylformamide (250 mL) was stirred at 60 to 70° C. for 3 hours.2-Bromoethyl methyl ether (5.00 g, 36 mmol) was further added thereto,and the reaction mixture was stirred at 60 to 70° C. for 2 hours andthen stirred overnight at room temperature. The reaction mixture waspoured into water (600 mL), followed by extraction with ethylacetate/toluene (1:1, 500 mL×2). The organic layer was washed with a 5%aqueous potassium carbonate solution and water in this order, and thesolvent was distilled off under reduced pressure to obtain the titlecompound (3-2-1) (20.2 g, quantitative).

Compound (3-2-2): Methyl 4-amino-3-(2-methoxyethoxy)benzoate

The compound (3-2-1) (20.2 g, 76 mmol) was subjected to atmospherichydrogenation reaction at room temperature for 2 hours in methanol (200mL) over 10% palladium carbon (8.06 g, 10 mol %). The termination ofhydrogen absorption was confirmed, and the catalyst was filtered off.The filtrate was concentrated under reduced pressure to obtain the titlecompound (3-2-2) (16.7 g, 98%).

Compound (3-2-3): Methyl 4-bromo-3-(2-methoxyethoxy)benzoate

A solution of the compound (3-2-2) (10.0 g, 44 mmol) in 48% aqueoushydrobromic acid (50 mL) was cooled in an ice bath. A solution of sodiumnitrite (3.07 g, 45 mmol) in water (30 mL) was added dropwise theretoover 30 minutes, and the reaction mixture was stirred for 1 hour. Thissolution kept at 5° C. or lower was added dropwise over 20 minutes to asolution of copper(I) bromide (4.17 g, 29 mmol) in 48% aqueoushydrobromic acid (50 mL) heated to 60° C., and the reaction mixture wasstirred at 60° C. for 1 hour. The mixture was cooled to room temperatureand then poured into water (400 mL), followed by extraction with diethylether. The organic layer was washed with water and brine in this order.The organic layer was dried over anhydrous magnesium sulfate, and thesolvent was then distilled off under reduced pressure. The obtainedconcentrated residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1) to obtain the title compound (3-2-3) (9.77g, 76%).

Compound (3-2-4): [4-Bromo-3-(2-methoxyethoxy)phenyl]methanol

A solution of the compound (3-2-3) (10.0 g, 35 mmol) in anhydroustetrahydrofuran (50 mL) was gradually heated under reflux, while a 1.0 Msolution of borane/tetrahydrofuran complex in tetrahydrofuran (140 mL,140 mmol) was added dropwise thereto. The reaction mixture was heatedunder reflux for 20 hours. After cooling to room temperature, water wasadded thereto until the gas evolution ceased. The tetrahydrofuran wasdistilled off under reduced pressure. An aqueous saturated sodiumbicarbonate solution was added to the concentrated residue, followed byextraction with chloroform. The organic layer was dried over anhydroussodium sulfate, and the solvent was then distilled off under reducedpressure. The obtained concentrated residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=1:1) to obtain the titlecompound (3-2-4) (9.13 g, quantitative).

Compound (3-1-4):

Carbon tetrabromide (15.5 g, 48 mmol) was added at the solutiontemperature of 20° C. or lower to a solution of the compound (3-2-4)(9.00 g, 34.5 mmol) and triphenylphosphine (10.9 g, 41 mmol) indichloromethane (200 mL) with ice cooling, and the reaction mixture wasstirred for 1.5 hours with ice cooling. The solvent was distilled offunder reduced pressure. The obtained concentrated residue was purifiedby silica gel column chromatography (chloroform) to obtain the titlecompound (3-1-4) (9.88 g, 88%).

Compound (3-1-5):

A solution of the compound (3-1-4) (9.85 g, 30 mmol) andtriphenylphosphine (9.57 g, 36.5 mmol) in toluene (200 mL) was heatedunder reflux for 16 hours. The reaction mixture was gradually cooled toroom temperature and subsequently stirred for 30 minutes in an ice bath,and the resulting precipitate was then collected by filtration, washedwith toluene (10 mL×2), and dried under reduced pressure to obtain thetitle compound (3-1-5) (19.4 g, quantitative).

Compound (3-1-6):

A suspension of the compound (3-1-5) (19.0 g, 32 mmol),1-tert-butoxycarbonyl-4-piperidone (7.10 g, 36 mmol), and potassiumcarbonate (6.71 g, 49 mmol) in 2-propanol (200 mL) was heated underreflux for 11.5 hours. The reaction mixture was cooled to roomtemperature, and the salt was then filtered off. The filtrate wasconcentrated under reduced pressure. n-Hexane/ethyl acetate (4:1, 200mL) was added to the obtained concentrated residue, and the resultingtriphenylphosphine oxide was filtered off. The filtrate was concentratedunder reduced pressure. The obtained concentrated residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=4:1) toobtain the title compound (3-1-6) (14.2 g, quantitative).

Compound (3-1-7):

The compound (3-1-6) (4.00 g, 9.4 mmol) was subjected to atmospherichydrogenation reaction at room temperature for 2.5 hours in ethylacetate (100 mL) over 5% rhodium carbon (1.91 g, 10 mol %). The catalystwas filtered off. The filtrate was concentrated under reduced pressure.The obtained concentrated residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound(3-1-7) (3.88 g, 97%).

Compound (RE3):

A 10% hydrochloric acid-methanol solution (20 mL) was added at roomtemperature to a solution of the compound (3-1-7) (3.88 g, 9.1 mmol) inmethanol (5 mL), and the reaction mixture was stirred at roomtemperature for 5 hours. The solvent was distilled off under reducedpressure. The obtained concentrated residue was solidified by theaddition of a small amount of 2-propanol and triturated with diethylether. The precipitate was collected by filtration and washed withdiethyl ether to obtain the compound (RE3) of interest (2.45 g, 74%).

Production Method 3

Compound (3-3-1): (4-Bromo-3-fluorobenzyl)(triphenyl)phosphonium bromide

A solution of 4-bromo-3-fluorotoluene (25.0 g, 132 mmol),5,5-dimethyl-1,3-dibromohydantoin (18.9 g, 66.1 mmol), andazobisisobutyronitrile (1.09 g, 6.64 mmol) in chlorobenzene (400 mL) wasstirred at the solution temperature of 80 to 90° C. for 1 hour. Thereaction mixture was cooled in an ice bath. Then, water (200 mL) andsodium thiosulfate (33 g, 132 mmol) were added thereto, and the mixturewas stirred. The mixture was separated into aqueous and organic layers.The organic layer was washed with water (200 mL), then dried overanhydrous sodium sulfate, and then concentrated until the whole volumereached approximately 100 mL. Triphenylphosphine (34.69 g, 132 mmol) andchlorobenzene (30 mL) were added thereto, and the mixture was heatedunder reflux for 3 hours. The reaction mixture was cooled to roomtemperature. Then, the precipitate was collected by filtration, washedwith toluene and then dried under reduced pressure to obtain the titlecompound (3-3-1) (47.0 g).

Compound (3-3-2): tert-Butyl4-[(4-bromo-3-fluorophenyl)methylidene]piperidine-1-carboxylate

A solution of the compound (3-3-1) (15.0 g, 28.3 mmol),1-tert-Butoxycarbonyl-4-piperidone (3.76 g, 18.9 mmol), and potassiumcarbonate (5.21 g, 37.7 mmol) in 2-propanol (28 mL) was heated underreflux for 3 hours. The reaction mixture was cooled to room temperature,and the salt was filtered off. Then, toluene (300 mL) was added to thefiltrate. The organic layer was washed with water (100 mL) and brine(100 mL). After drying over anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure. n-Hexane (107 mL) was added to theconcentrated residue, and the mixture was heated under reflux for 1hour. Then, the mixture was cooled to room temperature and stirred for 1hour. Then, the mixture was stirred for 1 hour with cooling in an icebath. The deposited triphenylphosphine oxide was separated by filtrationand washed with n-hexane. Then, the filtrate was concentrated underreduced pressure to obtain the title compound (3-3-2) (8.08 g) as ayellow solid.

Compound (3-3-3): tert-Butyl4-(4-bromo-3-fluorobenzyl)piperidine-1-carboxylate

The compound (3-3-2) (8.08 g) was subjected to atmospheric hydrogenationreaction for hours in ethyl acetate (57 mL) over 5% platinum carbon (800mg). The catalyst was filtered off through celite. The filtrate wasconcentrated to obtain the title compound (3-3-3) (8.61 g) as a paleyellow solid.

Compound (3-1-7):

Potassium t-butoxide (4.23 g, 37.7 mmol) was added at room temperatureto a solution of the compound (3-3-3) (8.61 g, which corresponds to 18.9mmol) and 2-methoxyethanol (2.98 mL, 37.7 mmol) inN-methyl-2-pyrrolidinone (38 mL), and the reaction mixture was stirredat the solution temperature of 90° C. for 2.5 hours. Then, potassiumt-butoxide (1.06 g, 9.43 mmol) was added thereto, and the mixture wasstirred at 90° C. for 30 minutes. Potassium t-butoxide (1.06 g, 9.43mmol) was further added thereto, and the mixture was stirred at 90° C.for 30 minutes. The reaction mixture was cooled in an ice bath, and anaqueous saturated ammonium chloride solution (80 mL) was added thereto,followed by extraction with toluene (80 mL×3). The combined organiclayers were washed with water (40 mL×2) and brine (40 mL) and dried overanhydrous magnesium sulfate, and the solvent was then distilled offunder reduced pressure. n-Hexane (162 mL) was added to the concentratedresidue, and the mixture was heated to 60° C. The dissolution thereofwas confirmed, and the solution was then gradually cooled to roomtemperature and stirred overnight at room temperature. Then, the mixturewas cooled in an ice bath and stirred for 1 hour. The deposit wascollected by filtration, washed with n-hexane and then dried underreduced pressure to obtain the title compound (3-1-7) (6.34 g) as alight brown powder.

Compound (RE3):

A 10% hydrochloric acid-methanol solution (24 mL) was added at roomtemperature to a solution of the compound (3-1-7) (6.00 g, 14.0 mmol) inmethanol (24 mL), and the reaction mixture was stirred at 50° C. for 5hours. After cooling to room temperature, the solvent was distilled offunder reduced pressure. To the concentrated residue, acetonitrile (6 mL)was added, and concentration under reduced pressure was repeated 4times. Acetonitrile (38 mL) was added to the concentrated residue, andthe mixture was heated in an oil bath at 80° C. The dissolution of thesolid matter was confirmed, and the solution was then cooled to roomtemperature over 1 hour. The solution was cooled in an ice bath andstirred at 20° C. for 1 hour and then in an ice bath for 1 hour. Then,the precipitate was collected by filtration, washed with coldacetonitrile (30 mL), and dried under reduced pressure to obtain thetitle compound (RE3) (4.56 g, 89%) as a white powder.

Reference Example 4 4-[4-Chloro-3-(2-methoxyethoxy)benzyl]piperidine,compound (RE4)

The compound was synthesized according to the following productionmethod:

Production Method

Compound (4-1): Methyl 4-chloro-3-(2-methoxyethoxy)benzoate

A solution of the compound (3-2-2) (5.20 g, 23 mmol) in concentratedhydrochloric acid (36%, 50 mL) was cooled in an ice bath. A solution ofsodium nitrite (1.59 g, 23 mmol) in water (20 mL) was added dropwisethereto over 10 minutes, and the reaction mixture was stirred for 20minutes. This solution kept at 5° C. or lower was added dropwise over 10minutes to a solution of copper(I) chloride (1.51 g, 15 mmol) inconcentrated hydrochloric acid (36%, 50 mL) warmed to 60° C., and thereaction mixture was stirred at 60° C. for 50 minutes. The mixture wascooled to room temperature and then diluted with water, followed byextraction with diethyl ether. The organic layer was washed with anaqueous saturated sodium bicarbonate solution and brine in this orderand dried over anhydrous magnesium sulfate, and the solvent was thendistilled off under reduced pressure. The obtained concentrated residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=4:1→1:1) to obtain the title compound (4-1) (4.43 g, 78%) as awhite solid.

Compound (4-2): [4-Chloro-3-(2-methoxyethoxy)phenyl]methanol

A 1.0 M solution of borane/tetrahydrofuran complex in tetrahydrofuran(106 mL, 106 mmol) was added dropwise at room temperature to a solutionof the compound (4-1) (4.33 g, 18 mmol) in anhydrous tetrahydrofuran (50mL), and the reaction mixture was subsequently heated under reflux for27.5 hours. After cooling to room temperature, methanol was addedthereto until the gas evolution ceased. The solvent was distilled offunder reduced pressure. The obtained concentrated residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=3:1→1:1) toobtain the title compound (4-2) (3.62 g, 94%).

Compound (4-3): 4-(Bromomethyl)-1-chloro-2-(2-methoxyethoxy)benzene

Triphenylphosphine (6.54 g, 25 mmol) and carbon tetrabromide (8.26 g, 25mmol) were simultaneously added at room temperature to a solution of thecompound (4-2) (3.60 g, 16.6 mmol) in diethyl ether (50 mL), and thereaction mixture was stirred for 16 hours. The precipitate was separatedby filtration. The filtrate was concentrated under reduced pressure. Theobtained concentrated residue was purified by silica gel columnchromatography (n-hexane-n-hexane:ethyl acetate=7:1) to obtain the titlecompound (4-3) (3.93 g, 85%) as a colorless oil.

Compound (4-4):[4-Chloro-3-(2-methoxyethoxy)benzyl](triphenyl)phosphonium bromide

A solution of the compound (4-3) (3.90 g, 14 mmol) andtriphenylphosphine (4.41 g, 36.17 mmol) in toluene (100 mL) was heatedunder reflux for 5 hours. The reaction mixture was gradually cooled toroom temperature and subsequently stirred for 1 hour in an ice bath.Then, the precipitate was collected by filtration, washed with toluene,and dried under reduced pressure to obtain the title compound (4-4)(7.24 g, 95%) as a white powder.

Compound (4-5): tert-Butyl4-{[4-chloro-3-(2-methoxyethoxy)phenyl]methylidene}piperidine-1-carboxylate

A suspension of the compound (4-4) (7.24 g, 13 mmol),1-tert-butoxycarbonyl-4-piperidone (2.40 g, 12 mmol), and potassiumcarbonate (2.78 g, 20 mmol) in 2-propanol (100 mL) was heated underreflux for 8 hours. The reaction mixture was stirred for 1 hours withice cooling. Then, the deposit was filtered off. The filtrate wasconcentrated under reduced pressure. The obtained concentrated residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=10:1→8:1) to obtain the title compound (4-5) (4.52 g,quantitative) as a colorless oil.

Compound (4-6): tert-Butyl4-[4-chloro-3-(2-methoxyethoxy)benzyl]piperidine-1-carboxylate

The compound (4-5) (4.52 g, 12 mmol) was subjected to atmospherichydrogenation reaction at room temperature for 1.5 hours in ethylacetate (200 mL) over 5% rhodium carbon (1.53 g). The catalyst wasfiltered off through celite. The filtrate was concentrated under reducedpressure. Then, the obtained concentrated residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=8:1→4:1) to obtain thetitle compound (4-6) (4.34 g, 96%).

Compound (RE4):

A solution of the compound (4-6) (4.34 g, 11 mmol) in 1,4-dioxane (50mL) was added to a 4 N hydrochloric acid-1,4-dioxane solution (50 mL),and the reaction mixture was stirred at room temperature for 15.5 hours.The solvent was distilled off under reduced pressure to obtain ahydrochloride of the title compound (3.24 g, 90%). A 2 g aliquot thereofwas added to a 2 N aqueous sodium hydroxide solution, followed byextraction with chloroform. The organic layer was dried over anhydroussodium sulfate, and the solvent was then concentrated under reducedpressure to obtain the compound (RE4) of interest (1.91 g) as a paleyellow oil.

Retention time (Condition 1): 13.71 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.03-1.26 (2H, m), 1.48-1.69 (3H, m), 2.48(2H, t, J=5.2 Hz), 2.54 (2H, td, J=12.5, 2.6 Hz), 3.06 (2H, br d, J=11.9Hz), 3.49 (3H, s), 3.80 (2H, t, J=4.8 Hz), 4.17 (2H, t, J=4.8 Hz), 6.69(1H, dd, J=7.9, 1.8 Hz), 6.73 (1H, d, J=1.8 Hz), 7.26 (1H, d, J=8.1 Hz).

Reference Example 5 (2-[2-Bromo-5-(piperidin-4-ylmethyl)phenoxy]ethanol,compound (RE5)

A solution of the compound (RE3) (3.00 g, 8.3 mmol) in dichloromethane(100 mL) was cooled in a salt-ice bath. A 1 M borontribromide-dichloromethane solution (7.8 mL, 7.8 mmol) was addeddropwise thereto at 0° C. over 30 minutes, and the reaction mixture wasstirred for 1.5 hours with ice cooling. Methanol (20 mL) was addedthereto, and the solvent was distilled off under reduced pressure. A 5%aqueous potassium carbonate solution (50 mL) was added to the obtainedconcentrated residue, followed by extraction with chloroform. Theorganic layer was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure to obtain the title compound (RE5)(3.03 g, quantitative).

Retention time (Condition 1): 7.56 minutes

¹H-NMR (400 MHz, CDCl₃) δ: 1.15-1.30 (2H, m), 1.40-1.55 (1H, m),1.55-1.70 (2H, m), 2.49 (2H, d, J=6.7 Hz), 2.58 (2H, dt, J=2.4, 12 Hz),3.11 (2H, d like, J=12 Hz), 3.98 (2H, t, J=4.6 Hz), 4.14 (2H, t, J=4.6Hz), 6.66 (1H, dd, J=8.0, 1.8 Hz), 6.70 (1H, d, J=1.8 Hz), 7.42 (1H, d,J=8.0 Hz).

Reference Example 6 4-[3-(2-Methoxyethoxy)-4-methylbenzyl]piperidine,compound (RE6)

The compound was synthesized according to the following productionmethod:

Production Method

Compound (6-1): tert-Butyl4-[3-(2-methoxyethoxy)-4-methylbenzyl]piperidine-1-carboxylate

A solution of the compound (3-1-7) (5.00 g, 11.7 g), methylboronic acid(978 mg, 16 mmol), and tetrakis(triphenylphosphine)palladium (674 mg, 5mol %) in 1 M aqueous potassium carbonate solution (35 mL) and1,4-dioxane (80 mL) was heated under reflux for 4 hours. After coolingto room temperature, the 1,4-dioxane was distilled off under reducedpressure. Water was added to the obtained concentrated residue, followedby extraction with ethyl acetate. The combined organic layers werewashed with brine and then dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure. Then, the concentratedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=4:1) to obtain the title compound (6-1) (3.46 g, 82%).

Compound (RE6):

A 10% hydrochloric acid-methanol solution (40 mL) was added at roomtemperature to the compound (6-1) (3.46 g, 9.5 mmol), and the reactionmixture was stirred overnight. The methanol was distilled off underreduced pressure, and an aqueous saturated sodium bicarbonate solutionwas added to the obtained concentrated residue, followed by salting-outand extraction with chloroform. The organic layer was dried overanhydrous sodium sulfate, and the solvent was then distilled off underreduced pressure to obtain the compound (RE6) of interest (2.56 g,quantitative).

¹H-NMR (300 MHz, CDCl₃) δ: 1.39-1.58 (2H, m), 1.58-1.74 (1H, m), 1.77(2H, d like, J=13.9 Hz), 2.20 (3H, s), 2.52 (2H, d, J=7.1 Hz), 2.70 (2H,t like, J=12.6 Hz), 3.33 (2H, d like, J=12.4 Hz), 3.47 (3H, s), 3.77(2H, t, J=4.8 Hz), 4.10 (2H, t, J=4.8 Hz), 6.59 (1H, s), 6.63 (1H, d,J=7.6 Hz), 7.03 (1H, d, J=7.6 Hz).

Reference Example 7 (2-(4-Oxo-3,4-dihydro-2H-chromen-6-yl)ethyl4-methylbenzenesulfonate, compound (RE7)

The compound was synthesized according to the following ProductionMethod 1, 2, or 3:

Production Method 1

Compound (7-1-1): Methyl [4-(3-hydroxypropoxy)phenyl]acetate

Potassium carbonate (91.5 g, 662 mmol) and 3-bromo-1-propanol (35.3 mL,391 mmol) were added in this order at room temperature to a solution of4-hydroxyphenylacetic acid methyl ester (50.0 g, 301 mmol) inacetonitrile (1000 mL) and water (10 mL), and the reaction mixture washeated under reflux for 3 hours. After cooling to room temperature, thesalt was filtered off, and the residue on the filter was washed withacetonitrile (50 mL×2). The filtrate was concentrated under reducedpressure, and the obtained concentrated residue was separated intoaqueous and organic layers by addition of toluene (500 mL) and water(250 mL). The aqueous layer was extracted with toluene (125 mL×2). Thecombined organic layers were washed with a 0.5 N aqueous sodiumhydroxide solution (100 mL) and a 1% aqueous potassium bisulfatesolution (100 mL). The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was then distilled off under reduced pressureto obtain the title compound (7-1-1) (70.2 g) as a yellow oil.

Compound (7-1-2): 3-[4-(2-Methoxy-2-oxoethyl)phenoxy]propanoic acid

A 0.25 M aqueous potassium dihydrogen phosphate solution (400 mL), a0.25 M aqueous disodium hydrogen phosphate solution (400 mL), 80% sodiumchlorite (54.5 g, 482 mmol), and a 5% aqueous sodium hypochloritesolution (6.52 mL, 4.82 mmol) were added in this order to a solution ofa 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) (4.71 g, 30.1mmol) in acetonitrile (160 mL). Subsequently, a solution of the compound(7-1-1) (56.2 g, which corresponds to 241 mmol) in acetonitrile (800 mL)was added dropwise thereto over approximately 1 hour with the solutiontemperature kept at 20 to 25° C. by water cooling. The reaction mixturewas stirred at this temperature for 2 hours. Then, a 20% aqueous sodiumbisulfite solution (400 mL) was added dropwise thereto over 30 minuteswith the solution temperature kept at 15° C. or lower by ice cooling.The solution was gradually warmed to room temperature, and theacetonitrile was distilled off under reduced pressure. Water (400 mL)was added thereto, and the mixture was stirred at room temperature for30 minutes. The resulting precipitate was collected by filtration andwashed with water (100 mL×2). The precipitate on the filter wasdissolved in ethyl acetate (400 mL), then washed with brine (100 mL),and dried over anhydrous sodium sulfate, and the solvent was thendistilled off under reduced pressure to obtain the title compound(7-1-2) (47.87 g).

Compound (7-1-3): Methyl [4-(3-chloro-3-oxopropoxy)phenyl]acetate

Thionyl chloride (42.7 mL, 592 mmol) was added at room temperature to asolution of the compound (7-1-2) (47.0 g, 197 mmol) in toluene (470 mL),and the reaction mixture was stirred at 60° C. for 3 hours. Aftercooling to room temperature, the toluene was distilled off to obtain thetitle compound (7-1-3) (56.52 g) as a pale yellow oil.

Compound (7-1-4): Methyl (4-oxo-3,4-dihydro-2H-chromen-6-yl)acetate

A solution of the compound (7-1-3) (56.52 g, which corresponds to 197mmol) in dichloromethane (140 mL) was added dropwise over 30 minutes toa solution of aluminum chloride (52.5 g, 394 mmol) in dichloromethane(330 mL) with the solution temperature kept at 20 to 25° C. by watercooling, and the reaction mixture was stirred at this temperature for1.5 hours. The reaction mixture was cooled, and a 2 N aqueoushydrochloric acid solution (470 mL) was added thereto with the solutiontemperature kept at 15° C. or lower by cooling in an ice bath. Themixture was warmed to room temperature and then separated into aqueousand organic layers. The aqueous layer was extracted with chloroform (120mL). The combined organic layers were washed with water (240 mL) and anaqueous saturated sodium bicarbonate solution (240 mL) in this order anddried over anhydrous magnesium sulfate, and the solvent was thendistilled off under reduced pressure to obtain the title compound(7-1-4) (38.91 g) as a brown solid.

Compound (7-1-5): Methyl(4,4-dimethoxy-3,4-dihydro-2H-chromen-6-yl)acetate

p-Toluenesulfonic acid monohydrate (3.02 g, 15.9 mmol) and Methylorthoformate (210 mL) were added to a solution of the compound (7-1-4)(35.0 g, 159 mmol) in methanol (105 mL), and the reaction mixture wasstirred at room temperature (15 to 20° C.) for 20 hours. The reactionsolution was added dropwise over 15 minutes to a 5% aqueous sodiumbicarbonate solution (175 mL) with the solution temperature kept at 15°C. or lower by ice cooling, and the mixture was separated into aqueousand organic layers by the addition of toluene (175 mL) and water (88mL). The aqueous layer was extracted with toluene (88 mL). The combinedorganic layers were washed with water (44 mL) and then dried overanhydrous sodium sulfate. The solvent was distilled off to obtain thetitle compound (7-1-5) (46.49 g) as a yellow oil.

Compound (7-1-6): 6-(2-Hydroxyethyl)-2,3-dihydro-4H-chromen-4-one

A solution of the compound (7-1-5) (46.0 g, which corresponds to 159mmol) in tetrahydrofuran (90 mL) was added dropwise over 30 minutes to asuspension of lithium aluminum hydride (9.05 g, 239 mmol) intetrahydrofuran (600 mL) with the solution temperature kept at 30° C. orlower by water cooling, and the reaction mixture was stirred at thistemperature for 1 hour. Tetrahydrofuran-water (1:2, 12 mL) was addeddropwise thereto with the solution temperature kept at 15° C. or lowerby ice cooling (during which insoluble matter was deposited and madestirring difficult). Subsequently, a 3 N aqueous hydrochloric acidsolution (460 mL) was added dropwise thereto with the solutiontemperature kept at 15° C. or lower. The mixture was directly stirred at20 to 25° C. for 1.5 hours and separated into aqueous and organic layersby the addition of toluene (460 mL). The aqueous layer was extractedwith toluene (230 mL). The combined organic layers were washed with a 3N aqueous hydrochloric acid solution (230 mL×2) and dried over anhydrousmagnesium sulfate, and the solvent was then distilled off under reducedpressure to obtain the title compound (7-1-6) (30.0 g) as a colorlessoil.

Compound (RE7):

Trimethylamine hydrochloride (497 mg, 5.20 mmol) and triethylamine (14.4mL, 104 mmol) were added to a solution of the compound (7-1-6) (10.0 g,which corresponds to 52 mmol) in acetonitrile (150 mL).p-Toluenesulfonyl chloride (11.9 g, 62.4 mmol) was added thereto insmall portions at the solution temperature of 15° C. or lower by coolingin an ice bath, and the reaction mixture was stirred at the solutiontemperature of 5° C. or lower for 1.5 hours. A 5% aqueous sodiumbicarbonate solution (75 mL) was added thereto at the solutiontemperature of 10° C. or lower, and the mixture was heated to roomtemperature and then separated into aqueous and organic layers by theaddition of toluene (75 mL). The aqueous layer was extracted withtoluene (75 mL). The combined organic layers were washed with a 1%aqueous potassium bisulfate solution (38 mL×2) and dried over anhydrousmagnesium sulfate, and the solvent was then distilled off under reducedpressure to obtain a concentrated residue (16.61 g). Toluene (50 mL) wasadded thereto, and the mixture was stirred at 50° C. for 1.5 hours andsubsequently cooled to room temperature (20 to 25° C.) over 30 minutes.The mixture was stirred at the solution temperature of 20 to 25° C. for1 hour by water cooling. Then, the precipitate was collected byfiltration, then washed with toluene (10 mL×2), and dried under reducedpressure to obtain the compound (RE7) of interest (10.65 g) as a paleyellow powder.

Retention time (Condition 2): 15.50 minutes

Melting point: 121-122° C.

¹H-NMR (300 MHz, CDCl₃) δ: 2.44 (3H, s), 2.79 (2H, t, J=6.5 Hz), 2.91(2H, t, J=6.9 Hz), 4.18 (2H, t, J=6.9 Hz), 4.51 (2H, t, J=6.4 Hz), 6.88(1H, d, J=8.4 Hz), 7.26 (1H, dd, J=8.5, 2.5 Hz), 7.30 (2H, d, J=8.5 Hz),7.60 (1H, d, J=2.2 Hz), 7.71 (2H, d, J=8.3 Hz).

Production Method 2

Compound (7-2-1): 3-[4-(2-Methoxyethyl)phenoxy]propan-1-ol

A solution of 4-(2-Methoxyethyl)phenol (1.00 g, 6.57 mmol),3-Bromo-1-propanol (771 μL, 8.54 mmol), potassium carbonate (2.00 g,14.5 mmol), and water (200 μL) in acetonitrile (20 mL) was heated underreflux for 3 hours. After cooling to room temperature, the salt wasseparated by filtration. The filtrate was concentrated under reducedpressure. The obtained concentrated residue was separated into aqueousand organic layers by the addition of water (5 mL) and toluene (5 mL).The aqueous layer was extracted with toluene (5 mL×2). The combinedorganic layers were washed with a 0.5 N aqueous sodium hydroxidesolution (2 mL) and 1% potassium bisulfate (2 mL) and dried overanhydrous sodium sulfate, and the solvent was then distilled off underreduced pressure to obtain the title compound (7-2-1) (1.56 g).

Compound (7-2-2): 3-[4-(2-Methoxyethyl)phenoxy]propanoic acid

The title compound (7-2-2) (1.30 g, 88%) was obtained as a white powderusing the compound (7-2-1) (1.56 g, which corresponds to 6.57 mmol) inthe same way as in Example (7-1-2).

Compound (7-2-3): 6-(2-Methoxyethyl)-2,3-dihydro-4H-chromen-4-one

Thionyl chloride (1.25 mL) was added at room temperature to a solutionof the compound (7-2-2) (1.30 g, 5.80 mmol) in toluene (13 mL), and thereaction mixture was stirred at 60° C. for 3 hours. After cooling toroom temperature, the solvent was distilled off under reduced pressureto obtain acid chloride (1.46 g). A solution of a 292 mg (whichcorresponds to 1.16 mmol) aliquot thereof in dichloromethane (1 mL) wasadded dropwise at room temperature over 5 minutes to a suspension ofaluminum chloride (309 mg, 2.32 mmol) in dichloromethane (2 mL) withwater cooling, and the reaction mixture was stirred for 1 hour. Thereaction solution was poured into a 2 N aqueous hydrochloric acidsolution (3 mL) and ice, followed by extraction with toluene. Theorganic layer was washed with water, an aqueous saturated sodiumbicarbonate solution, and brine in this order and dried over anhydroussodium sulfate, and the solvent was then distilled off under reducedpressure to obtain the title compound (7-2-3) (235 mg).

Compound (7-2-4): 2-(4-Oxo-3,4-dihydro-2H-chromen-6-yl)ethyl2,2-dimethylpropanoate

Pivaloyl chloride (298 μL, 2.43 mmol) was added at 40° C. to a solutionof the compound (7-2-3) (100 mg, 0.485 mmol), sodium iodide (436 mg,2.91 mmol), and water (3 μL) in acetonitrile (0.6 mL), and the reactionmixture was stirred at 40° C. for 1.5 hours. The mixture was cooled toroom temperature, then diluted with toluene, and separated into aqueousand organic layers by the addition of water. The aqueous layer wasextracted with toluene. The combined organic layers were washed with anaqueous saturated sodium bicarbonate solution and brine in this orderand dried over anhydrous sodium sulfate, and the solvent was thendistilled off under reduced pressure to obtain the title compound(7-2-4) (148 mg) as a brown oil.

Compound (7-1-6):

A solution of the compound (7-2-4) (105 mg, 0.354 mmol) in concentratedhydrochloric acid (36%, 2 mL) and methanol (1 mL) was stirred at 50° C.for 3 hours. The reaction mixture was cooled to room temperature andthen poured into ice, followed by extraction with toluene. The organiclayer was washed with an aqueous saturated sodium bicarbonate solutionand brine. The organic layer was dried over anhydrous sodium sulfate,and the solvent was then distilled off under reduced pressure to obtainthe title compound (7-1-6) (62 mg).

Compound (RE7):

p-Toluenesulfonyl chloride (81 mg, 0.43 mmol) was added to a solution ofthe compound (7-1-6) (62 mg, 0.354 mmol), trimethylamine hydrochloride(3.4 mg, 0.035 mmol), and triethylamine (98 μL) in dichloromethane (1mL) with cooling in an ice bath, and the reaction mixture was stirred atthis temperature for 1.5 hours. An aqueous saturated sodium bicarbonatesolution was added thereto, and the mixture was warmed to roomtemperature, followed by extraction with toluene. The combined organiclayers were washed with a 1% aqueous potassium bisulfate solution andbrine and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. Then, toluene (1 mL) was added tothe obtained concentrated residue, and the mixture was stirred at 50° C.for 1 hour. The mixture was gradually cooled to room temperature, whileit was stirred. Then, the mixture was stirred at room temperature for 2hours. The precipitate was collected by filtration, washed with toluene,and then dried under reduced pressure to obtain the compound (RE7) ofinterest (35 mg, 29%).

Production Method 3

Compound (7-3-1): 6-(Bromomethyl)-2,3-dihydro-4H-chromen-4-one

A solution of 6-Methyl-2,3-dihydro-4H-chromen-4-one (7.2 g, 44 mmol),5,5-Dimethyl-1,3-dibromohydantoin (7.7 g, 27 mmol), andAzobisisobutyronitrile (1.5 g, 9 mmol) in monochlorobenzene (140 mL) wasstirred at 80° C. for 3 hours. The reaction solution was poured into icewater (100 mL), and the mixture was warmed to room temperature and thenseparated into aqueous and organic layers. The aqueous layer wasextracted with dichloromethane (50 mL×2). The combined organic layerswere washed with brine. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was then distilled off under reducedpressure. The obtained concentrated residue was purified by silica gelcolumn chromatography (n-hexane/ethyl acetate) to obtain the titlecompound (7.8 g, 73%).

Compound (7-3-2): (4-Oxo-3,4-dihydro-2H-chromen-6-yl)acetonitrile

A solution of the compound (7-3-1) (500 mg, 2.1 mmol) and potassiumcyanide (135 mg, 2.1 mmol) in 1,4-dioxane (7.5 mL) and water (2.5 mL)was stirred at 50° C. for 3 hours. The reaction solution was cooled toroom temperature, and brine (30 mL) was then added thereto, followed byextraction with toluene (30 mL×2). The combined organic layers weredried over anhydrous magnesium sulfate, and the solvent was thendistilled off under reduced pressure. The obtained concentrated residuewas purified by silica gel column chromatography (n-hexane/ethylacetate) to obtain the title compound (311 mg, 70%).

Compound (7-1-4):

A solution of the compound (7-3-2) (276 mg, 1.5 mmol) in concentratedsulfuric acid (2 mL), acetic acid (2 mL), and water (2 mL) was stirredat 80° C. for 5 hours. The reaction solution was cooled to roomtemperature and then adjusted to pH 10 to 11 with a 10% aqueous sodiumhydroxide solution, followed by extraction with dichloromethane (30mL×2). The combined organic layers were washed with brine and then driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure to obtain a crude product of the compound (7-3-3)(4-oxo-3,4-dihydro-2H-chromen-6-yl)acetic acid. This crude product wasdissolved together with concentrated sulfuric acid (0.05 mL) in methanol(5 mL) without further purification, and the reaction mixture was heatedunder reflux for 2 hours. After cooling to room temperature, water (10mL) was added thereto, and the methanol was distilled off under reducedpressure. The concentrated residue was subjected to extraction withethyl acetate (30 mL×2). The combined organic layers were washed withbrine and dried over anhydrous magnesium sulfate, and the solvent wasthen distilled off under reduced pressure. The obtained concentratedresidue was purified by silica gel column chromatography (n-hexane/ethylacetate) to obtain the title compound (251 mg, 88%).

Compound (7-3-4): Methyl2,3-dihydrospiro[chromene-4,2′-[1,3]dioxolan]-6-ylacetate

A solution of the compound (7-1-4) (419 mg, 1.9 mmol), ethylene glycol(0.21 mL, 3.8 mmol), Methyl orthoformate (0.42 mL, 3.8 mmol), andp-Toluenesulfonic acid monohydrate (72 mg, 0.38 mmol) in toluene (8 mL)was heated under reflux for 3 hours. After cooling to room temperature,toluene (10 mL) was added thereto, and the mixed solution was washedwith an aqueous saturated sodium bicarbonate solution (10 mL), water,and brine in this order. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was then distilled off under reducedpressure to obtain a crude product of the title compound (502 mg).

Compound (7-1-6):

A solution of the compound (7-3-4) (502 mg) in tetrahydrofuran (3 mL)was added dropwise at 0° C. to a suspension of lithium aluminum hydride(72 mg, 1.9 mmol) in tetrahydrofuran (5 mL). The reaction mixture wasgradually warmed to room temperature, while it was stirred for 1 hour.Diethyl ether (8 mL) and water were added thereto, and the resultingprecipitate was separated by filtration. The solvent in the filtrate wasdistilled off under reduced pressure. A 10% aqueous hydrochloric acidsolution (8 mL) and tetrahydrofuran (8 mL) were added to the obtainedconcentrated residue, and the mixed solution was stirred at roomtemperature for 30 minutes. The tetrahydrofuran was distilled off underreduced pressure, followed by extraction with ethyl acetate. The organiclayer was distilled off under reduced pressure with brine and then driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The obtained concentrated residue was purifiedby silica gel column chromatography (n-hexane/ethyl acetate) to obtainthe title compound (254 mg, 69%).

Compound (RE7):

The compound (RE7) was obtained in the same way as in Production Method1 in Reference Example 7 using the compound (7-1-6).

Reference Example 8 2-(8-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl)ethyl4-methylbenzenesulfonate, compound (RE8)

The compound was synthesized according to the following productionmethod:

Production Method

Compound (8-1): 7-(2-Hydroxyethyl)-1,2,3,4-tetrahydronaphthalen-1-ol

A solution of (8-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetic acid (50mg, 0.25 mmol) synthesized according to a method described in thedocument (J. Med. Chem. 1994, 37 (21), 3485) in anhydroustetrahydrofuran (1 mL) was added to a suspension of lithium aluminumhydride (33 mg, 0.86 mmol) in anhydrous tetrahydrofuran (2 mL) underheating to reflux, and the reaction mixture was heated under reflux for1 hour. The reaction solution was cooled to room temperature and thencooled in an ice bath, and water (32 μL) was added thereto.Subsequently, a 15% aqueous sodium hydroxide solution (32 μL) and water(96 μL) were added thereto, and the solution was stirred at thistemperature for 30 minutes. The resulting precipitate was filtered off.The filtrate was concentrated to obtain the title compound (8-1) (45 mg,95%).

Compound (8-2): 7-(2-Hydroxyethyl)-3,4-dihydronaphthalen-1(2H)-one

A suspension of the compound (8-1) (45 mg, 0.23 mmol) and manganesedioxide (20 mg, 2.3 mmol) in dichloromethane (2 mL) was stirred at roomtemperature for 5 days. The manganese dioxide was filtered off. Thefiltrate was concentrated under reduced pressure. The obtainedconcentrated residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1) to obtain the title compound (8-2) (28 mg,63%).

Compound (RE8):

A solution of the compound (8-2) (28 mg, 0.15 mmol), triethylamine (41μL, 0.29 mmol), and triethylamine hydrochloride (1.4 mg, 0.015 mmol) indichloromethane (2 mL) was cooled in an ice bath. p-Toluenesulfonylchloride (42 mg, 0.22 mmol) was added thereto, and the reaction mixturewas stirred for 40 minutes with ice cooling. Water (20 mL) was addedthereto, followed by extraction with chloroform (40 mL×2). The organiclayer was dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure. The obtained concentrated residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=5:1→2:1) to obtain the compound (RE8) of interest (49 mg, 96%).

Retention time (Condition 2): 22.59 minutes

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, J=2.0 Hz, 1H, Ar), 7.71 (d, J=8.4 Hz,2H, Ar), 7.32-7.26 (m, 3H, Ar), 7.17 (d, J=7.7 Hz, 1H, Ar), 4.20 (t,J=7.0 Hz, 2H, CH2), 3.00-2.90 (m, 4H), 2.64 (5, J=6.5 Hz, 2H, CH2), 2.44(s, 3H, CH3), 2.18-2.08 (m, 2H).

Reference Example 9 2-(3-Oxo-2,3-dihydro-1H-inden-5-yl)ethyl4-methylbenzenesulfonate, compound (RE9)

The title compound (RE9) was produced in the same way as in ReferenceExample 8 using (3-Oxo-2,3-dihydro-1H-inden-5-yl)acetic acid producedaccording to a method described in the document (J. Med. Chem. 1979, 22(12), 1464).

¹H-NMR (300 MHz, CDCl₃) δ: 7.69 (d, J=8.5 Hz, 2H, Ar), 7.44 (s, 1H, Ar),7.41-7.38 (m, 2H, Ar), 7.28 (d, J=8.5 Hz, 2H, Ar), 4.22 (t, J=6.8 Hz,2H, CH2), 3.11 (5, J=6.0 Hz, 2H, CH2), 3.01 (t, J=6.8 Hz, 2H, CH2), 2.69(t, J=6.0 Hz, 2H, CH2), 2.44 (s, 3H, CH3).

Reference Example 10 2-(5-Oxo-2,3,4,5-tetrahydro-1-benzoxepin-7-yl)ethyl4-methylbenzenesulfonate, compound (RE10)

The title compound (RE10) was produced in the same way as in ReferenceExample 8 using (5-Oxo-2,3,4,5-tetrahydro-1-benzoxepin-7-yl)acetic acidproduced according to a method described in the patent document(JP-A-61-236774).

Retention time (Condition 2): 19.93 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 2.16-2.25 (2H, m), 2.44 (3H, s), 2.81-2.99(4H, m), 4.13-4.27 (4H, m), 6.98 (1H, d, J=8.3 Hz), 7.21 (1H, dd, J=8.3,2.3 Hz), 7.30 (2H, d, J=8.1 Hz), 7.48 (1H, d, J=2.4 Hz), 7.72 (2H, d,J=8.3 Hz).

Reference Example 11 (2-(4-Oxo-3,4-dihydro-2H-chromen-6-yl)ethylbenzenesulfonate), compound (RE11)

The title compound was obtained in the same way as in Production Method1 in Reference Example 7 using the compound (7-1-6) and benzenesulfonylchloride.

¹H-NMR (300 MHz, CDCl₃) δ: 2.85 (2H, t, J=6.2 Hz), 2.90 (2H, t, J=7.0Hz), 4.19 (2H, t, J=7.0 Hz), 4.22 (2H, t, J=6.2), 6.79 (2H, d, J=8.6Hz), 7.01 (2H, d, J=8.6 Hz), 7.45-7.52 (2H, m), 7.57-7.65 (1H, m),7.75-7.82 (2H, m).

Example 1(6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one

A solution of the compound (RE3) (99 mg, 0.30 mmol), the compound (RE9)(100 mg, 0.30 mmol), and potassium carbonate (0.39 mmol) in acetonitrile(3 mL) was stirred at 60° C. for 27 hours. The reaction mixture wascooled to room temperature, and water (20 mL) was then added thereto,followed by extraction with ethyl acetate (40 mL). The organic layer wasdried over anhydrous sodium sulfate, and the solvent was then distilledoff under reduced pressure. The obtained concentrated residue waspurified by preparative thin-layer silica gel chromatography(chloroform:methanol=10:1) to obtain the title compound (137 mg, 93%) asa pale yellow oil.

Retention time (Condition 1): 27.44 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.33 (2H, m), 1.44-1.71 (3H, m), 1.97 (2H,bt, J=9.9 Hz), 2.49 (2H, d, J=6.8 Hz), 2.58 (2H, bt, J=8.1 Hz),2.67-2.73 (2H, m), 2.88 (2H, bt, J=8.0 Hz), 2.99 (2H, bd, J=11.2 Hz),3.11 (2H, t, J=5.9 Hz), 3.50 (3H, s), 3.81 (2H, dd, J=5.3, 4.2 Hz), 4.17(2H, dd, J=5.3, 4.2 Hz), 6.64 (1H, dd, J=8.1, 1.8 Hz), 6.71 (1H, d,J=1.8 Hz), 7.37-7.47 (3H, m), 7.58 (1H, bs).

Example 27-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one

The title compound was synthesized in the same way as in Example 1 usingthe compound (RE8) instead of the compound (RE9).

Retention time (Condition 1): 31.95 minutes

¹H-NMR (400 MHz, CDCl₃) δ: 1.26-1.37 (2H, m), 1.46-1.54 (1H, m), 1.64(2H, bd, J=12.2 Hz), 1.95 (2H, dt, J=16.2, 5.8 Hz), 2.09-2.15 (2H, m),2.49 (2H, d, J=7.1 Hz), 2.55 (2H, bt, J=8.4 Hz), 2.64 (2H, t, J=6.6 Hz),2.81 (2H, bt, J=8.4 Hz), 2.93 (2H, t, J=6.6 Hz), 2.96 (2H, d, J=12.2Hz), 3.50 (3H, s), 3.81 (2H, dd, J=5.5, 4.3 Hz), 4.17 (2H, dd, J=5.5,4.3 Hz), 6.64 (1H, dd, J=8.0, 2.0 Hz), 6.71 (1H, d, J=2.0 Hz), 7.17 (1H,d, J=7.8 Hz), 7.32 (1H, dd, J=7.8, 1.8 Hz), 7.41 (1H, d, J=8.0 Hz), 7.86(1H, d, J=1.8 Hz).

Example 3(6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one

The compound (RE3) (52.0 g, 143 mmol) was added to a 5% aqueouspotassium carbonate solution (350 mL), followed by extraction withtoluene (700 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidine (48.1 g). Next, asolution of the 4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidine (2.00 g,6.1 mmol), the compound (RE7) (2.01 g, 5.8 mmol), and potassiumcarbonate (1.66 g, 12 mmol) in acetonitrile (20 mL) was stirred at 70 to80° C. for 7 hours. After cooling to room temperature, water (100 mL)was added thereto, followed by extraction with chloroform. Thechloroform layer was dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure. Then, the obtainedconcentrated residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1→chloroform:methanol=20:1) to obtain thetitle compound (3.07 g, quantitative).

Retention time (Condition 1): 29.11 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.24-1.39 (2H, m), 1.40-1.73 (3H, m), 1.93(2H, t, J=10.6 Hz), 2.40-2.61 (2H, m), 2.48 (2H, d, J=7.2 Hz), 2.66-2.87(2H, m), 2.79 (2H, t, J=6.4 Hz), 2.95 (2H, d, J=11.7 Hz), 3.49 (3H, s),3.81 (2H, t, J=4.9 Hz), 4.17 (2H, t, J=4.9 Hz), 4.51 (2H, t, J=6.4 Hz),6.64 (1H, dd, J=8.1, 1.8 Hz), 6.71 (1H, d, J=1.8 Hz), 6.89 (1H, d, J=8.4Hz), 7.32 (1H, dd, J=8.4, 2.2 Hz), 7.41 (1H, d, J=8.1 Hz), 7.70 (1H, d,J=2.2 Hz).

Example 46-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onehydrochloride

An aqueous concentrated hydrochloric acid solution (36%, 760 μL, 8.5mmol) was added at room temperature to a solution of the compound (3.07g, 5.8 mmol) obtained in Example 3 in 2-propanol (20 mL), and thesolution was stirred at room temperature for 15.5 hours. The precipitatewas collected by filtration, washed with 2-propanol (2 mL×2), and driedunder reduced pressure to obtain the title compound (2.26 g, 72%) as awhite powder.

Melting point: 156-157° C.

Example 56-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate

A solution of the compound (1.00 g, 2.0 mmol) obtained in Example 3 andbenzenesulfonic acid monohydrate (316 mg, 2.0 mmol) in 2-propanol (5 mL)was heated to 70° C. The dissolution of the solid matter was confirmed,and the solution was then stirred with cooling to room temperature over4 hours. The resulting precipitate was collected by filtration, thenwashed with 2-propanol (1 mL×2), and then dried under reduced pressureto obtain a crude product of the title compound (1.13 g). A 500 mgaliquot thereof was added to a mixed solution of acetone (10 mL) andwater (100 μL), and the mixture was heated. The dissolution thereof wasconfirmed, and the solution was then gradually cooled and stirred at 35to 40° C. for 1 hour. Then, the solution was further cooled and stirredat 20 to 25° C. for 1 hour. The precipitate was collected by filtrationand washed with acetone (1 mL) to obtain the title compound (323 mg).

Melting point: 143-144° C.

Compounds shown in Examples 6 to 20 below were produced by the samesynthetic method as in Example 1. The corresponding compounds wereappropriately selected from among the compounds (RE1) to (RE10) shown inReference Examples and used as starting materials.

Example 67-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydro-1-benzoxepin-5(2H)-one

Retention time (Condition 1): 30.84 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.25-1.42 (2H, m), 1.44-1.72 (3H, m), 1.96(2H, bt, J=11.0 Hz), 2.15-2.24 (2H, m), 2.49 (2H, d, J=7.0 Hz), 2.55(2H, bdd, J=9.9, 5.7 Hz), 2.79 (2H, bdd, J=9.9, 5.7 Hz), 2.89 (2H, t,J=6.9 Hz), 2.99 (2H, bd, J=11.0 Hz), 3.50 (3H, s), 3.81 (2H, dd, J=5.3,4.2 Hz), 4.14-4.25 (4H, m), 6.64 (1H, dd, J=8.0, 1.8 Hz), 6.71 (1H, d,J=1.8 Hz), 6.99 (1H, d, J=8.3 Hz), 7.27 (1H, dd, J=8.3, 2.5 Hz), 7.41(1H, d, J=8.1 Hz), 7.58 (1.0H, d, J=2.5 Hz).

Example 76-(2-{4-[4-Chloro-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one

Retention time (Condition 1): 27.43 minutes

¹H-NMR (400 MHz, CDCl₃) δ: 1.23-1.37 (2H, m), 1.43-1.56 (1H, m),1.60-1.78 (2H, m), 1.94 (2H, t like, J=12 Hz), 2.49 (2H, d, J=7.2 Hz),2.50-2.55 (2H, m), 2.72-2.80 (2H, m), 2.79 (2H, t, J=6.4 Hz), 2.96 (2H,d like, J=11.5 Hz), 3.49 (3H, s), 3.81 (2H, t, J=4.8 Hz), 4.18 (2H, t,J=4.8 Hz), 4.51 (2H, t, J=6.4 Hz), 6.69 (1H, dd, J=8.0, 1.8 Hz), 6.74(1H, d, J=1.8 Hz), 6.89 (1H, d, J=8.5 Hz), 7.24 (1H, d, J=8.0 Hz), 7.31(1H, dd, J=8.5, 2.2 Hz), 7.70 (1H, d, J=2.2 Hz).

Example 86-(2-{4-[3-(2-Methoxyethoxy)-4-methylbenzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one

Retention time (Condition 1): 25.84 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.20-1.60 (3H, m), 1.66 (2H, d, J=13.0 Hz),1.95 (2H, t, J=11.7 Hz), 2.21 (3H, s), 2.49 (2H, d, J=7.0 Hz), 2.53-2.58(2H, m), 2.69 (2H, t, J=5.9 Hz), 2.86 (2H, t, J=8.6 Hz), 2.96 (2H, d,J=11.4 Hz), 3.10 (2H, t, J=6.1 Hz), 3.47 (3H, s), 3.78 (2H, t, J=4.6Hz), 4.12 (2H, t, J=5.5 Hz), 6.62 (1H, s), 6.65 (1H, d, J=7.9 Hz), 7.03(1H, d, J=7.5 Hz), 7.39 (1H, d, J=7.9 Hz), 7.44 (1H, d, J=7.9 Hz), 7.58(1H, s).

Example 97-(2-{4-[3-(2-Methoxyethoxy)-4-methylbenzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one

Retention time (Condition 1): 30.36 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.30-1.80 (5H, m), 1.99 (2H, t, J=11.9 Hz),2.12 (2H, quint, J=6.2 Hz), 2.21 (3H, s), 2.50 (2H, d, J=6.6 Hz),2.54-2.70 (4H, m), 2.80-2.90 (2H, m), 2.93 (2H, t, J=5.9 Hz), 3.01 (2H,d, J=10.8 Hz), 3.47 (3H, s), 3.78 (2H, t, J=4.6 Hz), 4.12 (2H, t, J=5.5Hz), 6.61 (1H, s), 6.65 (1H, d, J=7.5 Hz), 7.03 (1H, d, J=7.5 Hz), 7.18(1H, d, J=7.7 Hz), 7.33 (1H, dd, J=1.5, 7.9 Hz), 7.86 (1H, d, J=1.7 Hz).

Example 106-(2-{4-[3-(2-Methoxyethoxy)-4-methylbenzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one

Retention time (Condition 1): 27.01 minutes

¹H-NMR (CDCl₃) δ: 1.20-1.41 (2H, m), 1.43-1.73 (3H, m), 1.93 (2H, tlike, J=10.9 Hz), 2.20 (3H, s), 2.41-2.62 (2H, m), 2.49 (2H, d, J=7.1Hz), 2.67-2.87 (4H, m), 2.95 (2H, d, J=10.7 Hz), 3.47 (3H, s), 3.77 (2H,t, J=4.8 Hz), 4.12 (2H, t, J=4.9 Hz), 4.51 (2H, t, J=6.3 Hz), 6.61 (1H,s), 6.65 (1H, d, J=7.6 Hz), 6.89 (1H, d, J=8.5 Hz), 7.03 (1H, d, J=7.6Hz), 7.32 (1H, dd, J=8.4, 2.3 Hz), 7.70 (1H, d, J=2.2 Hz).

Example 116-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one

Retention time (Condition 1): 17.50 minutes

¹H-NMR (400 MHz, CDCl₃) δ: 1.38-1.26 (2H, m), 1.46-1.68 (3H, m), 1.96(2H, bt, J=11.1 Hz), 2.50 (2H, d, J=7.1 Hz), 2.57 (2H, bt, J=7.8 Hz),2.67-2.71 (2H, m), 2.86 (2H, bt, J=7.8 Hz), 2.98 (2H, bd, J=11.1 Hz),3.10 (2H, bt, J=5.9 Hz), 3.99 (2H, bt, J=4.5 Hz), 4.15 (2H, bt, J=4.5Hz), 6.67 (1H, dd, J=8.0, 1.7 Hz), 6.71 (1H, d, J=1.7 Hz), 7.39 (1H, d,J=7.8 Hz), 7.42 (1H, d, J=8.0 Hz), 7.44 (1H, dd, J=7.8, 1.5 Hz), 7.58(1H, bs).

Example 127-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one

Retention time (Condition 1): 21.91 minutes

¹H-NMR (400 MHz, CDCl₃) δ: 1.24-1.39 (2H, m), 1.46-1.70 (3H, m), 1.95(2H, bt, J=12.2 Hz), 2.09-2.15 (2H, m), 2.50 (2H, d, J=7.1 Hz),2.51-2.59 (2H, m), 2.64 (2H, t, J=6.6 Hz), 2.78-2.83 (2H, m), 2.93 (2H,t, J=6.6 Hz), 2.96 (2H, d, J=12.2 Hz), 3.99 (2H, bt, J=4.4 Hz), 4.15(2H, t, J=4.5 Hz), 6.67 (1H, dd, J=8.0, 2.0 Hz), 6.71 (1H, d, J=2.0 Hz),7.17 (1H, d, J=7.8 Hz), 7.31 (1H, dd, J=7.8, 2.0 Hz), 7.42 (1H, d, J=8.0Hz), 7.86 (1H, d, J=2.0 Hz).

Example 136-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one

Retention time (Condition 1): 18.91 minutes

¹H NMR (300 MHz, CDCl₃) δ: 1.28-1.42 (2H, m), 1.62-1.78 (1H, m), 1.66(2H, bd, J=12.7 Hz), 2.00 (2H, bt, J=11.6 Hz), 2.50 (2H, d, J=7.0 Hz),2.58 (2H, dd, J=11.0, 7.7 Hz), 2.76-2.81 (4H, m), 3.01 (2H, bd, J=11.6Hz), 3.99 (2H, bt, J=4.5 Hz), 4.15 (2H, bd. J=4.5 Hz), 4.51 (2H, t,J=6.8 Hz), 6.66 (1H, dd, J=8.1, 1.8 Hz), 6.71 (1H, d, J=1.8 Hz), 6.90(1H, d, J=8.5 Hz), 7.33 (1H, dd, J=8.5, 2.4 Hz), 7.42 (1H, d, J=8.1 Hz),7.70 (1H, d, J=2.4 Hz).

Example 147-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydro-1-benzoxepin-5(2H)-one

Retention time (Condition 1): 20.89 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.25-1.45 (2H, m), 1.44-1.70 (3H, m), 1.96(2H, bt, J=11.2 Hz), 2.15-2.24 (2H, m), 2.50 (2H, d, J=6.6 Hz), 2.54(2H, bdd, J=9.9, 6.1 Hz), 2.78 (2H, bdd, J=9.9, 6.1 Hz), 2.89 (2H, t,J=6.6 Hz), 2.98 (2H, bd, J=11.2 Hz), 3.99 (2H, bt, J=4.4 Hz), 4.15 (2H,t, J=4.4 Hz), 4.21 (2H, t, J=6.6 Hz), 6.67 (1H, dd, J=8.1, 2.0 Hz), 6.71(1H, d, J=2.0 Hz), 6.99 (1H, d, J=8.3 Hz), 7.26 (1H, dd, J=8.3, 2.4 Hz),7.42 (1H, d, J=8.1 Hz), 7.58 (1H, d, J=2.4 Hz).

Example 156-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one

Retention time (Condition 1): 27.89 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.24-1.42 (2H, m), 1.46-1.70 (3H, m), 1.97(2H, bt, J=10.3 Hz), 2.47 (2H, d, J=7.0 Hz), 2.58 (2H, bt, J=7.8 Hz),2.67-2.71 (2H, m), 2.87 (2H, bt, J=7.8 Hz), 2.98 (2H, bd, J=10.3 Hz),3.11 (2H, t, J=5.9 Hz), 3.45 (3H, s), 3.72-3.75 (2H, m), 4.07-4.10 (2H,m), 6.66 (1H, td, J=1.9, 0.3 Hz), 6.89-6.92 (2H, m), 7.39 (1H, d, J=8.0Hz), 7.45 (1H, dd, J=8.0, 1.6 Hz), 7.58 (1H, d, J=1.6 Hz).

Example 167-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydronaphthalen-1(2H)-one

Retention time (Condition 1): 32.39 minutes

¹H-NMR (400 MHz, CDCl₃) δ: 1.28-1.40 (2H, m), 1.46-1.56 (1H, m), 1.64(2H, bd, J=12.6 Hz), 1.98 (2H, bt, J=11.0 Hz), 2.08-2.15 (2H, m), 2.46(2H, d, J=7.0 Hz), 2.52-2.60 (2H, m), 2.64 (2H, t, J=6.1 Hz), 2.80-2.87(2H, m), 2.93 (2H, t, J=6.1 Hz), 2.98 (2H, d, J=11.0 Hz), 3.45 (3H, s),3.73 (2H, t, J=4.6 Hz), 4.08 (2H, t, J=4.6 Hz), 6.66 (1H, bs), 6.88-6.92(2H, m), 7.17 (1H, dt, J=7.8 Hz), 7.32 (1H, dd, J=7.8, 1.7 Hz), 7.85(1H, d, J=1.7 Hz).

Example 176-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one

Retention time (Condition 1): 29.33 minutes

¹H-NMR (400 MHz, CDCl₃) δ: 1.26-1.37 (2H, m), 1.45-1.68 (3H, m), 1.94(2H, bt, J=11.5 Hz), 2.46 (2H, d, J=7.1 Hz), 2.49-2.55 (2H, m),2.73-2.81 (4H, m), 2.96 (2H, bd, J=11.5 Hz), 3.45 (3H, s), 3.72-3.75(2H, m), 4.07-4.11 (2H, m), 4.51 (2H, t, J=6.3 Hz), 6.62 (1H, bt, J=1.8Hz), 6.88-6.90 (3H, m), 7.32 (1H, dd, J=8.5, 2.3 Hz), 7.70 (1H, d, J=2.3Hz).

Example 187-(2-{4-[3-Bromo-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-3,4-dihydro-1-benzoxepin-5(2H)-one

Retention time (Condition 1): 31.43 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.25-1.41 (2H, m), 1.44-1.69 (3H, m), 1.96(2H, bt, J=11.6 Hz), 2.15-2.24 (2H, m), 2.46 (2H, d, J=7.0 Hz), 2.54(2H, bdd, J=9.9, 6.4 Hz), 2.79 (2H, bdd, J=9.9, 6.4 Hz), 2.89 (2H, t,J=7.0 Hz), 2.97 (2H, bd, J=11.6 Hz), 3.72-3.75 (2H, m), 3.45 (3H, s),4.07-4.10 (2H, m), 4.21 (2H, t, J=6.7 Hz), 6.66 (1H, t, J=1.8 Hz),6.88-6.92 (2H, m), 6.99 (1H, d, J=8.3 Hz), 7.27 (1H, dd, J=8.3, 2.4 Hz),7.58 (1H, d, J=2.4 Hz).

Example 196-(2-{4-[3-Chloro-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one

Retention time (Condition 1): 26.77 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.25-1.39 (2H, m), 1.47-1.58 (1H, m), 1.65(2H, bd, J=12.7 Hz), 1.96 (2H, bt, J=11.1 Hz), 2.47 (2H, d, J=7.1 Hz),2.55-2.59 (2H, m), 2.68-2.71 (2H, m), 2.84-2.88 (2H, m), 2.98 (2H, bd,J=11.5 Hz), 3.10 (2H, t, J=5.7 Hz), 3.45 (3H, s), 3.73-3.75 (2H, m),4.08-4.10 (2H, m), 6.62 (1H, bt, J=1.8 Hz), 6.73-6.77 (2H, m), 7.39 (1H,d, J=7.8 Hz), 7.44 (1H, dd, J=7.8, 1.7 Hz), 7.58 (1H, bs).

Example 206-(2-{4-[3-Chloro-5-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-one

Retention time (Condition 1): 28.33 minutes

¹H-NMR (300 MHz, CDCl₃) δ: 1.20-1.39 (2H, m), 1.45-1.58 (1H, m), 1.65(2H, bd, J=13.4 Hz), 1.96 (2H, bt, J=10.6 Hz), 2.47 (2H, d, J=7.0 Hz),2.50-2.59 (2H, m), 2.73-2.82 (4H, m), 2.98 (2H, bd, J=11.6 Hz), 3.45(3H, s), 3.72-3.76 (2H, m), 4.07-4.10 (2H, m), 4.51 (2H, t, J=6.4 Hz),6.62 (1H, bt, J=1.7 Hz), 6.73-6.78 (2H, m), 6.90 (1H, d, J=8.4 Hz), 7.32(1H, dd, J=8.4, 2.4 Hz), 7.70 (1H, d, J=2.4 Hz).

The structural formulae of the compounds of Examples 6 to 20 are shownin Table 1 below.

TABLE 1 General Formula:

Example No. R¹ R² X n 6 Me p-Br O 3 7 Me p-Cl O 2 8 Me p-Me CH₂ 1 9 Mep-Me CH₂ 2 10 Me p-Me O 2 11 H p-Br CH₂ 1 12 H p-Br CH₂ 2 13 H p-Br O 214 H p-Br O 3 15 Me m-Br CH₂ 1 16 Me m-Br CH₂ 2 17 Me m-Br O 2 18 Mem-Br O 3 19 Me m-Cl CH₂ 1 20 Me m-Cl O 2

Example 216-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onefumarate

A solution of the compound (503 mg, 1.00 mmol) obtained in Example 3 andfumaric acid (58 mg, 0.50 mmol) in ethanol (10 mL) was concentratedunder reduced pressure to obtain a concentrated residue (557 mg). A 100mg aliquot thereof was added to acetone (3 mL), and the mixture wasstirred at room temperature for 1 hour. Then, the precipitate wascollected by filtration and dried under reduced pressure to obtain thetitle compound (42 mg).

Melting point: 149-150° C.

Example 226-(2-{4-[4-Bromo-3-(2-hydroxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onehydrochloride

An aqueous concentrated hydrochloric acid solution (36%, 860 μL, 10mmol) was added at room temperature to a solution of the compound (3.96g, 8.1 mmol) obtained in Example 13 in 2-propanol (40 mL) anddichloromethane (50 mL), and the solvent was removed by concentrationunder reduced pressure. 2-Propanol (72 mL) was added to the obtainedconcentrated residue (3.61 g), and the mixture was heated under refluxfor 2 hours and stirred with cooling to 20° C. over 3 hours. The mixturewas stirred at 20° C. for 1 hour and then stirred for 1 hour with icecooling. The precipitate was collected by filtration and washed withcold 2-propanol (4 mL×2) to obtain a white solid (3.35 g). To this whitesolid, 2-propanol (100 mL) and aqueous concentrated hydrochloric acidsolution (36%, 500 μL) were added, and the mixture was heated to areflux temperature. The dissolution of the solid matter was confirmed,and the solution was then cooled to 60° C. Precipitation was confirmed,and the mixture was then stirred at 55 to 60° C. for 1 hour.Subsequently, the mixture was stirred with cooling to 20° C. over 2hours and then stirred at 20° C. for 1 hour. The precipitate wascollected by filtration and washed with 2-propanol (4 mL×2) to obtainthe title compound (3.10 g, 73%) as a white powder.

Melting point: 177-178° C.

Example 236-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onehydrobromide

A 48% aqueous hydrobromic acid solution (170 μL, 2.4 mmol) was addedwith ice cooling to a solution of the compound (1.00 g, 2.00 mmol)obtained in Example 3 in 2-propanol (10 mL), and the solution was warmedto room temperature and stirred overnight. The resulting precipitate wascollected by filtration, then washed with 2-propanol (1 mL×2), and thendried under reduced pressure to obtain a crude crystal of the titlecompound (797 mg). The crude crystal (750 mg) was added to 2-propanol(30 mL), and the mixture was heated under reflux. The dissolution of thesolid matter was confirmed. The solution was then gradually cooled toroom temperature, while it was stirred for 19 hours. The resultingprecipitate was collected by filtration, then washed with 2-propanol (1mL×2), and then dried under reduced pressure to obtain the titlecompound (613 mg) as a white crystalline solid.

Melting point: 148-150° C.

Example 246-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebutanedioate

The compound (218 mg, 0.43 mmol) obtained in Example 3 and Succinic acid(26 mg, 0.22 mmol) were added to ethanol (10 mL). The dissolutionthereof was confirmed, and the solvent was then distilled off underreduced pressure to obtain a concentrated residue (244 mg). Theconcentrated residue (105 mg) was stirred for 1 hour in2-butanone/n-hexane (1:1, 1 mL). The resulting precipitate was collectedby filtration and dried under reduced pressure at room temperature toobtain the title compound (36 mg, 62%) as a white powder.

Melting point: 100-101° C.

¹H-NMR (DMSO-d₆) δ: 1.10-1.25 (2H, m), 1.45-1.60 (3H, m), 1.94-2.07 (2H,m), 2.39 (4H, s), 2.47 (2H, d, J=6.6 Hz), 2.53-2.58 (2H, m), 2.68-2.75(2H, m), 2.76 (2H, t, J=6.5 Hz), 2.92-3.01 (2H, m), 3.34 (3H, s), 3.68(2H, t, J=4.5 Hz), 4.16 (2H, t, J=4.5 Hz), 4.50 (2H, t, J=6.3 Hz), 6.69(1H, dd, J=8.0, 1.5 Hz), 6.94 (1H, d, J=1.5 Hz), 6.95 (1H, d, J=8.5 Hz),7.42 (1H, dd, J=8.5, 2.4 Hz), 7.44 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.4Hz).

Example 256-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate

The compound (RE3) (10.0 g, 27.4 mmol) was added to an aqueous potassiumhydroxide solution (prepared from potassium hydroxide [2.15 g, 32.9mmol] and water [50 mL]), followed by extraction with toluene (50 mL×2).All the organic layers were combined, and the solvent was distilled offunder reduced pressure to obtain a concentrated residue 1. To thisconcentrated residue 1, the compound (RE11) (9.57 g, 28.8 mmol),dipotassium hydrogen phosphate (14.3 g, 82.3 mmol),N-methyl-2-pyrrolidinone (3.0 mL), and toluene (100 mL) were added, andthe mixture was stirred at 110 to 120° C. for 6.5 hours. After coolingto 40 to 50° C., water (100 mL), tetrahydrofuran (50 mL), and toluene(50 mL) were added thereto. The organic layer was washed with water (50mL). The solvent was distilled off under reduced pressure to obtain aconcentrated residue 2, which was in turn used in separate portions inthe subsequent reactions without further purification. A solution of a ⅕volume (which corresponds to 5.5 mmol) of the concentrated residue 2 inacetone (8 mL) was added at 40 to 50° C. to a suspension ofbenzenesulfonic acid ammonium (0.96 g, 5.48 mmol) in acetone (32 mL).The mixture was stirred at 50° C. for 1 hour. The complete dissolutionof the solid matter was confirmed, and the solvent was then distilledoff under reduced pressure. Acetone (20 mL) was added to theconcentrated residue, and the mixture was heated to 50° C. fordissolution. Then, a seed crystal (5.0 mg) was added thereto at 40° C.The mixture was stirred at 40° C. for 1 hour and gradually cooled toroom temperature. Then, the mixture was stirred for 3 hours in an icebath, and the precipitate was collected by filtration, washed with coldacetone (4.0 mL×2), and dried under reduced pressure to obtain the titlecompound (2.85 g, 79%).

Example 266-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate

A suspension of the compound (RE3) (30.0 g, 82.3 mmol), the compound(RE7) (29.9 g, 86.4 mmol), and potassium carbonate (34.11 g, 247 mmol)in acetonitrile (236 g) was heated under reflux for 6.5 hours. Thereaction mixture was cooled to room temperature and then separated intoaqueous and organic layers by the addition of toluene (519 g) and water(600 g). The organic layer was washed with water (300 g), and thesolvent was then distilled off under reduced pressure to obtain aconcentrated residue (44.6 g). Acetone (170 g) was added to theconcentrated residue, and the mixture was filtered. The residue on thefilter was washed with acetone (40 g). To all the filtrates, water (3 g)was added, and the mixture was warmed to 40° C. Benzenesulfonic acidmonohydrate (15.2 g, 96 mmol) and then a seed crystal (0.15 g) wereadded thereto, and the mixture was stirred at 40° C. for 1 hour.Subsequently, the mixture was gradually cooled to 2° C., while it wasstirred. The mixture was stirred at the solution temperature of 2° C.for 1 hour. Then, the precipitate was collected by filtration, washedwith cold acetone (47.5 g×2), and dried under reduced pressure at 40° C.to obtain the title compound (36.8 g, 68%) as a white crystalline solid.

Example 27 Form 1-type Crystal of6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onehydrochloride

The compound (RE3) (52.0 g, 143 mmol) was added to a 5% aqueouspotassium carbonate solution (350 mL), followed by extraction withtoluene (700 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidine (48.1 g). This compoundwas added together with the compound (RE7) (47.0 g, 143 mmol) andpotassium carbonate (37.5 g, 271 mmol) to acetonitrile (470 mL), and thereaction mixture was stirred at the solution temperature of 55 to 60° C.for 25 hours. The mixture was cooled to room temperature and thenseparated into aqueous and organic layers by the addition of water (940mL) and toluene (940 mL). The aqueous layer was extracted with toluene(470 mL). The combined organic layers were dried over anhydrous sodiumsulfate, and the solvent was then distilled off under reduced pressure.2-Propanol (1.1 L) was added to the obtained concentrated residue (76.6g). An aqueous concentrated hydrochloric acid solution (36%, 14 mL, 171mmol) was added dropwise thereto at 15 to 20° C. over 5 minutes withwater cooling, and the solution was stirred for 2 hours at 15 to 20° C.for 22 hours. Then, the solution was cooled in an ice bath and stirredfor 4.5 hours. The precipitate was collected by filtration, then washedwith cold 2-propanol (55 mL×2), and dried under reduced pressure toobtain a concentrated residue (61.6 g). To this concentrated residue,2-propanol (900 mL) and a 36% aqueous concentrated hydrochloric acidsolution (36%, 9.0 mL) were added, and the mixture was heated. Thecomplete dissolution thereof at around 60° C. was confirmed, and thesolution was then cooled to 20° C. and stirred at 15 to 20° C. for 14.5hours. Then, the solution was cooled in an ice bath and stirred for 5hours. The precipitate was collected by filtration, then washed withcold 2-propanol (70 mL×2), and dried under reduced pressure to obtainthe title compound (51.1 g, 70%) as a colorless crystalline solid.

Melting point: 157-159° C.

Elemental Analysis

TABLE 2 Element C H N Cl Br Found Ratio 57.72 6.07 2.72 6.46 14.71 (%)Theoretical 57.95 6.17 2.60 6.58 14.83 Ratio (%)

Example 28 Form A-type Crystal of6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate

A solution of the compound (1.00 g, 2.00 mmol) obtained in Example 3 andbenzenesulfonic acid (316 mg, 2.0 mmol) in 2-propanol (5 mL) was warmedto 70° C. The dissolution of the solid matter was confirmed, and thesolution was then stirred with cooling to room temperature over 4 hours.The resulting precipitate was collected by filtration, then washed with2-propanol (1 mL×2), and then dried under reduced pressure to obtain aconcentrated residue (1.13 g). A 1.05 g aliquot thereof was added to2-propanol (32 mL), and the mixed solution was heated under reflux. Thedissolution of the solid matter was confirmed, and the solution was thenstirred with cooling. A seed crystal (2 mg) was added thereto at 65° C.,and the mixture was stirred at 60 to 65° C. for 1 hour. Subsequently,the mixture was stirred with cooling to 30° C. over 2 hours and stirredfor 1 hour with water cooling (25° C.). Then, the precipitate wascollected by filtration, then washed with 2-propanol (2 mL×2), and thendried under reduced pressure to obtain the title compound (963 mg) as acolorless crystalline solid.

Melting point: 142-143° C.

Elemental Analysis

TABLE 3 Element C H N S Br Found Ratio 58.18 5.83 2.30 4.87 12.07 (%)Theoretical 58.18 5.80 2.12 4.85 12.10 Ratio (%)

Example 29 Form B-type Crystal of6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate

The compound (RE3) (2.00 g, 5.5 mmol) was added to a 10% aqueouspotassium carbonate solution (20 mL), followed by extraction withtoluene (20 mL×2). The solvent in the combined organic layers wasdistilled off under reduced pressure to obtain4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidine (1.95 g). Next, asolution of the 4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidine (1.95 g,5.5 mmol), the compound (RE7) (1.80 g, 5.2 mmol), and potassiumcarbonate (1.44 g, 10 mmol) in acetonitrile (10 mL) was stirred at 55 to60° C. for 19 hours. The reaction solution was cooled to roomtemperature, and water (30 mL) was then added thereto, followed byextraction with toluene (30 mL×3). The combined organic layers werewashed with a 5% aqueous sodium bicarbonate solution (30 mL) and water(30 mL) in this order, and the solvent was then distilled off underreduced pressure. The obtained concentrated residue was dissolved inacetone (40 mL), and benzenesulfonic acid monohydrate (1.06 g, 6.0 mmol)was added thereto. The dissolution of the solid matter was confirmed,and the solvent was then distilled off under reduced pressure. Acetone(40 mL) and water (0.4 mL) were added to the obtained concentratedresidue, and the mixture was heated to 40° C. A seed crystal (5 mg) wasadded thereto, and the mixture was stirred at 35 to 40° C. for 1.5hours. Subsequently, the mixture was cooled to 20° C. over 1 hour andthen stirred for 1 hour with ice cooling. The precipitate was collectedby filtration, then washed with cold acetone (5 mL×2), and then driedunder reduced pressure at room temperature to obtain the title compound(2.45 g, 71%) as a colorless crystalline solid.

Melting point: 143-144° C.

Elemental Analysis

TABLE 4 Element C H N S Br Found Ratio 58.09 5.80 2.25 4.85 12.10 (%)Theoretical 58.18 5.80 2.12 4.85 12.10 Ratio (%)

Example 30 Form C-type Crystal of6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate

The compound (7.76 g, 15.5 mmol) obtained in Example 3 was dissolved in1% (v/v) hydrated acetone (100 mL), and the solution was warmed to 40 to45° C. Then, benzenesulfonic acid monohydrate (2.93 g, 17 mmol) wasadded thereto, and the mixture was stirred. The dissolution of the solidmatter was confirmed. Then, a seed crystal (50 mg) was added thereto,and the mixture was stirred at 40 to 45° C. for 1 hour. Subsequently,the mixture was stirred with cooling to 25° C. over 3 hours and thenstirred at room temperature for 17.5 hours. Subsequently, the mixturewas cooled to 5° C. or lower over 1 hour and stirred at this temperaturefor 1 hour. The precipitation was collected by filtration, and theresidue on the filter was washed with cold acetone (10 mL×2) and thendried under reduced pressure to obtain the title compound (8.83 g, 88%)as a colorless crystalline solid.

Melting point: 143-145° C. (Transition to Form A occurred at 128° C.)

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.30-1.46 (2H, m), 1.72-1.86 (3H, m), 2.52(2H, d, J=6.4 Hz), 2.78 (2H, t, J=6.5 Hz), 2.82-3.00 (4H, m), 3.18-3.30(2H, m), 3.34 (3H, s), 3.48-3.58 (2H, m), 3.66-3.72 (2H, m), 4.12-4.20(2H, m), 4.51 (2H, t, J=6.5 Hz), 6.72 (1H, dd, J=8.1, 2.0 Hz), 6.96 (1H,d, J=2.0 Hz), 7.01 (1H, d, J=8.5 Hz), 7.27-7.34 (3H, m), 7.44 (1H, dd,J=8.5, 2.2 Hz), 7.47 (1H, d, J=8.1 Hz), 7.56-7.61 (2H, m), 7.67 (1H, d,J=2.2 Hz), 9.02 (1H, br s).

Elemental Analysis

TABLE 5 Element C H N S Br Found Ratio 58.42 5.83 2.26 4.86 12.11 (%)Theoretical 58.18 5.80 2.12 4.85 12.10 Ratio (%)

Example 31 Form A-type Crystal of6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onemonofumarate

The compound (3.0 g, 6.0 mmol) obtained in Example 3 was dissolved inethanol (75 mL), and a solution of fumaric acid (693 mg, 6.0 mmol) inethanol (25 mL) and further methanol (100 mL) were added thereto. Thedissolution thereof was confirmed, and the solvent was then distilledoff under reduced pressure to obtain a concentrated residue. To thisconcentrated residue, acetone (110 mL) was added, and the mixture wasstirred at room temperature for 2.5 hours. The resulting precipitate wascollected by filtration and dried under reduced pressure (40° C., 1mmHg, 18 hours) to obtain the title compound (3.26 g, 88%) as acolorless crystalline solid.

Melting point: 149-151° C.

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.17-1.40 (2H, m), 1.47-1.73 (3.0H, m),2.15-2.32 (2H, m), 2.48 (2H, d, J=6.4 Hz), 2.63-2.85 (6H, m), 3.05-3.17(2H, m), 3.34 (3H, s), 3.65-3.72 (2H, m), 4.13-4.20 (2H, m), 4.50 (2H,t, J=6.4 Hz), 6.56 (2H, s), 6.70 (1H, dd, J=8.0, 1.7 Hz), 6.95 (2H, d,J=1.7 Hz), 6.97 (2H, d, J=8.6 Hz), 7.42 (2H, dd, J=8.6, 2.2 Hz), 7.45(1H, d, J=8.0 Hz), 7.60 (1H, d, J=2.2 Hz).

Example 32 Form A+-type Crystal of6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onemonofumarate

The Form A-type crystal (500 mg) obtained in Example 31 was added to 1%hydrated acetone (25 mL), and the mixture was heated to 65° C. Thedissolution thereof was confirmed. Then, the solution was graduallycooled to room temperature, while it was stirred for 17 hours. Theresulting precipitate was collected by filtration and dried underreduced pressure (40° C., 1 mmHg, 24 hours) to obtain the title compound(403 mg, 80%) as a colorless crystalline solid.

Melting point: 148-149° C.

¹H-NMR: The same data as in Example 31 was obtained.

Example 336-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate

4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidine hydrochloride (2.0 g,5.48 mmol) was added to an aqueous potassium hydroxide solution(prepared from potassium hydroxide [0.43 g, 6.58 mmol] and water [10ml]), followed by extraction with toluene (10 ml×2). All the organiclayers were combined, and the solvent was distilled off under reducedpressure. 6-(2-p-Benzenesulfonyloxyethyl)-2,3-dihydro-4H-chromen-4-one(1.91 g, 5.76 mmol), dipotassium hydrogen phosphate (2.87 g, 16.5 mmol),N-methyl-2-piperidone (0.6 ml), and toluene (20 ml) were added to theconcentrated residue, and the mixture was stirred at 110 to 120° C. for6 hours. After cooling to 40 to 50° C., water (20 ml), tetrahydrofuran(10 ml), and toluene (10 ml) were added thereto. The organic layer waswashed with water (10 ml). The solvent was distilled off under reducedpressure to obtain a concentrated residue. The obtained concentratedresidue was dissolved in acetone (6.0 ml) without further purification,and a solution of benzenesulfonic acid (0.93 g, 5.76 mmol) in acetone(4.0 ml) was added dropwise thereto at 50 to 60° C. The mixture wasstirred at 50 to 60° C. for 30 minutes. Then, n-butyl acetate (20.0 ml)was added dropwise thereto, and the mixture was further stirred for 1hour. After cooling to room temperature, n-butyl acetate (10 ml) wasadded dropwise thereto, and the mixture was stirred for 3.5 hours in anice bath. The precipitate was collected by filtration, washed with coldacetone (4.0 ml×2), and dried under reduced pressure to obtain the titlecompound (3.21 g, 89%).

Example 34 Form C-type Crystal of6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate

0.5% Hydrated acetone (15.2 mL) was added to6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate (1.0 g, 1.51 mmol), and the compound was dissolved at50° C. or higher. The solution was cooled to 40 to 50° C. A seed crystal(Form C-type crystal obtained in Example 30) (5 mg) was added thereto,and the mixture was stirred at 40 to 50° C. for 1 hour. The mixture wascooled to room temperature and stirred at room temperature for 1 hour,and n-heptane (8.8 mL) was then added thereto. The mixture was stirredfor 3 hours in an ice bath. Then, the precipitate was collected byfiltration, then washed with acetone (2.5 mL), and then dried underreduced pressure at 50° C. to obtain the title compound (0.92 g, 92%) asa Form C-type crystal.

Test Example 1 Screening Test Using [³H]Citalopram Binding forEvaluating Human Serotonin Reuptake Inhibitory Effect 1-1 Cells Used andPreparation of Membrane Preparation

CHO cells containing a human serotonin transporter (h-SERT) expressedtherein (h-SERT/CHO) were used in the experiment. The cells werecultured in F12 containing 10% FCS, 500 μg/ml Geneticin, and 100 U/mlpenicillin-100 μg/ml streptomycin (all manufactured by Sigma-AldrichCorp.) in a 5% CO₂ incubator and dissociated/collected using a SERTbuffer (50 mM Tris-HCl (pH=7.4) containing 120 mM NaCl and 5 mM KCl).The resulting cells were homogenized using a Teflon (registeredtrademark) homogenizer and then centrifuged (50,000×g, 30 min, 4° C.).The pellet was resuspended in an appropriate amount of a SERT buffer andstored at −80° C. until use. The amount of the protein in the membranepreparation was quantified using Dye Reagent Concentrate (manufacturedby Bio-Rad Laboratories, Inc.) with bovine serum albumin (manufacturedby Sigma-Aldrich Corp.) as a standard.

1-2 Receptor Binding Experiment

[³H]Citalopram binding was measured according to the method of Owens etal. [Owens M. J. et al., J. Pharm. Exp. Ther., 283, 1305-1322 (1997)].Specifically, 50 μl of [³H]citalopram (final concentration:approximately 2 nM) diluted with a SERT buffer, 149 μl of the h-SERT/CHOmembrane preparation (40 μg/well in terms of the amount of the protein),and 1 μl of a solution of a test drug dissolved in dimethyl sulfoxidewere mixed to prepare 200 μl in total of a solution. This solution wasreacted at room temperature for 60 minutes and then rapidly filtered bysuction at a low pressure through glass fiber filter paper coated with a0.05% aqueous polyethyleneimine solution. The glass fiber filter paperwas washed twice with 250 μl of a SERT buffer and then transferred to aglass vial containing 4 ml of ACS-II (manufactured by AmershamBiosciences). Radioactivity remaining on the filter paper was measuredusing a liquid scintillation counter. The amount of [³H]citalopram boundin the presence of 1 μM clomipramine was used as the amount of[³H]citalopram bound non-specifically.

An IC₅₀ value was calculated according to the Hill analysis [see Hill A.V., J. Physiol., 40, 190-200 (1910)]. A h-SERT binding inhibitionconstant (Ki) was calculated according to the equation:

h-SERT binding inhibition constant (Ki)=IC ₅₀/(1+S/Kd)

wherein S represents the concentration of [³H]citalopram added; and theKd value represents the dissociation constant of [³H]citalopram, whereinthe Kd value used was the value (2.16 nM) calculated by a saturationbinding experiment separately conducted using the same cell membrane asabove.A smaller value of the h-SERT binding inhibition constant Ki means ahigher human serotonin reuptake inhibitory effect.

Test Example 2 [³H]8-OH-DPAT Binding Test for Evaluating Affinity forHuman Serotonin 1A Receptor 2-1 Cells Used and Preparation of MembranePreparation

CHO cells containing a human serotonin 1A receptor (h-5-HT_(1A))expressed therein (h-5-HT_(1A)/CHO) were used in the experiment. Thecells were cultured in F12 containing 10% FCS, 500 μg/ml Geneticin, and100 U/ml penicillin-100 μg/ml streptomycin (all manufactured bySigma-Aldrich Corp.) in a 5% CO₂ incubator. The membrane preparation wasprepared according to the method of Yabuuchi et al³). Specifically, thecells were dissociated/collected using 50 mM Tris-HCl (pH=7.4). Theresulting cells were homogenized using a Teflon (registered trademark)homogenizer and then centrifuged (48,000×g, 20 min, 4° C.). The pelletwas resuspended in an appropriate amount of 50 mM Tris-HCl (pH=7.4) andstored at −80° C. until use. The amount of the protein in the membranepreparation was quantified using Dye Reagent Concentrate (manufacturedby Bio-Rad Laboratories, Inc.) with bovine serum albumin (manufacturedby Sigma-Aldrich Corp.) as a standard.

2-2 Receptor Binding Experiment

The experiment was conducted according to the method of Yabuuchi et al.[Yabuuchi K. et al., Biogenic Amines, 18, 319-328 (2004)]. 50 μl of[³H]8-OH-DPAT (final concentration: 0.5 nM), 1 μl of a test drugsolution, and 149 μl of the h-5-HT_(1A)/CHO membrane preparation (25μg/well in terms of the amount of the protein) were added to a buffersolution containing 50 mM Tris-HCl (pH=7.4) and 4 mM CaCl₂, and 200 μlin total of the reaction solution was used in measurement. The reactionsolution was reacted at room temperature for 30 minutes and then rapidlyfiltered by suction at a low pressure through glass fiber filter paper.The glass fiber filter paper was washed twice with 250 μl of 50 mMTris-HCl (pH=7.4) and then added to a counting vial containing 4 ml ofACS-II (manufactured by Amersham Biosciences). Receptor bindingradioactivity remaining on the filter paper was measured using a liquidscintillation counter. The amount of [³H]8-OH-DPAT bound in the presenceof 10 μM 8-OH-DPAT was used as the amount of [³H]8-OH-DPAT boundnon-specifically.

An IC₅₀ value was calculated according to the Hill analysis [see Hill A.V., J. Physiol., 40, 190-200 (1910)]. A h-5-HT_(1A) binding inhibitionconstant (Ki) was calculated according to the equation:

h-5-HT_(1A) binding inhibition constant (Ki)=IC ₅₀/(1+S/Kd)

wherein S represents the concentration of [³H]8-OH-DPAT added; and theKd value represents the dissociation constant of [³H]8-OH-DPAT, whereinthe Kd value used was the value (1.28 nM) calculated by a saturationbinding experiment separately conducted using the same cell membrane asabove.A smaller value of the h-5-HT_(1A) binding inhibition constant Ki meanshigher affinity for human serotonin 1A receptors.

The benzylpiperidine compounds of the present invention obtained inExamples were subjected to the tests of Test Examples 1 and 2. Theresults are shown in Table 6. These test results demonstrated that thebenzylpiperidine compound of the present invention or thepharmaceutically acceptable salt thereof not only has a human serotoninreuptake inhibitory effect in combination with binding affinity forhuman 5-HT1A receptors but also has a high human serotonin reuptakeinhibitory effect.

TABLE 6 Test Example Test Example 1: h-SERT 2: h-5-HT_(1A) bindingbinding Compound inhibition inhibition (Example constant (Ki) constant(Ki) No.) [nM] [nM] 1 0.87 4.5 2 0.70 12 4 0.79 4.2 6 1.2 72 7 2.7 4.6 82.8 3.7 9 3.1 13 10 4.2 19 11 6.4 3.8 12 9.2 23 13 7.4 8.6 14 8.5 55 153.2 35 16 2.9 27 17 4.0 30 18 6.2 295 19 3.0 29 20 2.4 57

Test Example 3 CYP2D6 Inhibition Screening Test 3-1 Materials

Bufuralol was purchased from Sigma-Aldrich Corp., and Pooled of HumanLiver Microsomes was purchased from Xenotech, LLC.

3-2-1 Preparation of 0.5 M Potassium Phosphate Buffer (pH 7.4)

150 mL of a 0.5 M monopotassium phosphate solution and 700 mL of a 0.5 Mdipotassium phosphate solution were mixed to adjust pH 7.4.

3-2-2 Preparation of 165 mM Magnesium Chloride Solution

Magnesium chloride hexahydrate was dissolved at a concentration of 3.35g (MgCl₂.6H₂O)/100 mL in distilled water.

3-2-3 Preparation of Human Liver Microsome Solution

150 μL of Pooled Human Liver Microsomes (20 mg/ml), 12 mL of a 0.5 Mpotassium phosphate buffer, 1.2 mL of a 165 mM magnesium chloridesolution, and 34.65 mL of distilled water were mixed.

3-2-4 Preparation of 13 mM β-NADPH Solution

β-NADPH was dissolved at a concentration of 11.75 mg/mL in distilledwater.

3-2-5 Preparation of Substrate Solution

Bufuralol was dissolved at a concentration of 2.0 mM in DMSO and thendiluted 200-fold with distilled water.

3-3 Experimental Procedures

1. A 10 mM DMSO solution of a test drug was serially diluted 5-fold withDMSO for 4 serial dilutions to prepare 10, 2, 0.4, and 0.08 mM DMSOsolutions.2. Each test drug solution of the step 1. and DMSO were separatelydiluted 96-fold with a human liver microsome solution, and each dilutionwas dispensed and 80 μL of each dilution to microplates.3. 10 μL of a substrate solution and 10 μL of a β-NADPH solution wereadded to the well of the step 2., followed by incubation at 37° C. for10 min.4. The reaction was terminated by the addition of 300 μL of methanol.5. The reaction mixture was filtered, and LC-MSMS analysis wasconducted.

3-4 Quantification and Calculation

The amount of 1′-hydroxybufuralol produced was quantified by LC-MSMS,and this amount was used as a metabolic activity of CYP2D6 for eachwell. The remaining activity of each sample was determined by comparisonwith the activity obtained from DMSO as a test drug. An IC₅₀ value ofCYP2D6 inhibition was determined from the test drug concentration andremaining activity. The IC₅₀ value was calculated by linearinterpolation between two points that span the remaining activity 50%. Alarger value of IC₅₀ of CYP2D6 inhibition means weaker CYP2D6inhibition.

Test Example 4 Screening Test of the Rate of CYP2D6 Contribution inHuman Liver Microsomal Metabolism

0.2 mL of a 50 mM potassium phosphate buffer solution (pH 7.4)containing NADPH (final concentration: 3 mM, manufactured by OrientalYeast Co., Ltd.), 1 mg/mL human liver microsomes (manufactured byXENOTECH, LLC), and a 1 μM test substance was heated on a water bath at37° C. for metabolic reaction. After the reaction for 15 minutes or 30minutes, methanol was added in a volume 3 times that of the reactionsolution, and the mixture was stirred to terminate the reaction. Thisreaction solution was centrifuged for protein precipitation. Then, thesupernatant was collected and subjected to LC-MS/MS analysis. Theresults were analyzed as follows:

The test substance was quantified, and time-dependent change in theamount of the substance remaining was logarithmically plotted. Ametabolic rate was calculated from the slope.

The ratio of the metabolic rate obtained by the addition of quinidine(final concentration: 4 μM) to the reaction solution to the metabolicrate obtained without the addition was used as the rate of contributionof enzymes other than CYP2D6, and the rate of contribution obtained bysubtracting this rate of contribution of other enzymes from the totalwas used as the rate of CYP2D6 contribution. Specifically, it wascalculated according to the equation:

Rate of contribution (%)={1−(metabolic rate [with quinidine]/metabolicrate [without quinidine])}×100.

A smaller value of the rate of CYP2D6 contribution means smaller CYP2D6contribution.

The benzylpiperidine compounds of the present invention obtained inExamples were subjected to the tests of Test Examples 3 and 4. Theresults are shown in Table 7. These test results demonstrated that thebenzylpiperidine compound of the present invention or thepharmaceutically acceptable salt thereof has weaker CYP2D6 inhibitionand undergoes small CYP2D6 contribution to metabolism.

TABLE 7 Test Example Test Example 4: Rate of Compound 3: CYP2D6 CYP2D6(Example Inhibition Contribution No.) IC₅₀ [μM] [%] 1 27.9 36 2 12.8 124 22.9 0 6 24.7 4.2 7 17.5 54 8 31.0 9.6 9 33.7 7.8 10 21.5 49 11 24.6—*⁾ 12 27.9 17 13 26.9 —*⁾ 14 34.8 —*⁾ 15 36.1 11 16 26.3 9.2 17 24.6 1418 27.5 0 19 20.4 16 20 23.4 24 *⁾The rate of CYP2D6 contribution wasindeterminable in the present test due to high stability for humanmicrosomal metabolism.

Test Example 5 Serotonin Transporter Function Inhibition Test Using[³H]5-HT 1-1 Cells Used and Preparation of Cell Suspension

CHO cells containing a human serotonin transporter (h-SERT) expressedtherein (h-SERT/CHO) were used in the experiment. The cells werecultured in F12 containing 10% FCS, 500 μg/ml Geneticin, and 100 U/mlpenicillin-100 μg/ml streptomycin (all manufactured by Sigma-AldrichCorp.) in a 5% CO₂ incubator and dissociated/collected on the day of useusing Cell Dissociation Buffer (Enzyme-free, PBS-based, manufactured byGIBCO). The collected cells were suspended in a buffer solutioncontaining 0.1 mM CaCl₂ and 1 mM MgCl₂ in PBS (hereinafter, referred toas PBSCM) and stored in ice until use.

1-2 [³H]5-HT Uptake Test

[³H]5-HT uptake was measured according to the method of Roman et al.[Roman D. L. et al., J. Pharmacol. Exp. Ther., 308, 679-687 (2004); andHill A.V., J. Physiol., 40, 190-200 (1910)]. Specifically, 149 μl of thecell suspension (10×10⁴ cells/well) and 1 μl of a solution of a testdrug dissolved in dimethyl sulfoxide were preincubated at 37° C. for 10minutes. Then, 50 μl of [³H]5-HT (final concentration: approximately 10nM) diluted with PBSCM was added thereto to prepare 200 μl in total of asolution. This solution was reacted at 37° C. for 10 minutes and thenrapidly filtered by suction at a low pressure through glass fiber filterpaper coated with a 0.3% aqueous polyethyleneimine solution. The glassfiber filter paper was washed twice with 250 μl of an ice-cold salineand then transferred to a glass vial containing 4 ml of ACS-II(manufactured by Amersham Biosciences). Radioactivity remaining on thefilter paper was measured using a liquid scintillation counter. Theamount of [³H]5-HT uptaken in the presence of 13.3 μM paroxetine wasused as the amount of [³H]5-HT uptaken non-specifically.

An IC₅₀ value was calculated according to the Hill analysis [see HillA.V., J. Physiol., 40, 190-200 (1910)]. An uptake inhibition constant(Ki) was calculated according to the following equation:

Uptake inhibition constant (Ki)=IC ₅₀/(1+S/Km)

wherein S represents the concentration of [³H]5-HT added; and the Kmvalue represents the Michaelis constant of [³H]5-HT, wherein the Kmvalue used was the value (441 nM) calculated by a saturation experimentseparately conducted using the same cell preparation as above. Theresults are shown in Table 8.

TABLE 8 Test Example 5: h-SERT Function Inhibition Compound Constant(Ki) (Example No.) [nM] 1 8.9 2 1.6 4 4.2 6 1.6 7 16 10 44 13 51 17 18

The test results of Table 8 demonstrated that the benzylpiperidinecompound of the present invention or the pharmaceutically acceptablesalt thereof acts on serotonin transporters in serotonergic neurons andthereby strongly inhibit serotonin reuptake.

Test Example 6 X-Ray Powder Diffraction (XRPD) Analysis

An X-ray powder diffraction (XRPD) analyzer used was X′Pert Promanufactured by Spectris Co., Ltd. The measurement was conducted underconditions involving a diffraction angle (2θ) in the range of 4° to 40°,Cu Kα1 radiation (wavelength: 1.54060 Å), an X-ray tube current of 40mA, a voltage of 45 kV, a step of 0.01700°, and a measurement time of101.41770 seconds/step. The measurement was conducted usingapproximately 5 mg of a sample in a non-reflective sample plate made ofsilicon single crystals (Si single crystals).

Each crystal obtained in Examples 27 to 32 was subjected to the presentanalysis. The obtained X-ray powder diffraction patterns are shown inFIGS. 1 to 6. Their crystal forms can be identified by determinationfrom a diffraction peak characteristic of each crystal based on thediffraction pattern. The diffraction peak characteristic of each crystalidentified from the diffraction pattern will be described later. In thiscontext, a peak angle at the diffraction angle 2θ may have an errorrange to a certain degree depending on a measurement instrument ormeasurement conditions or the like. Specifically, a measurement errorrange of ±0.2, preferably ±0.1, is acceptable. On the other hand, thevalue of relative intensity may vary depending on the manner of samplepreparation, measurement conditions, or the like.

Table 9 shows a peak angle, d-spacing, and relative intensity thereof inthe X-ray powder diffraction of the Form 1-type crystal of6-(2-{4-[4-bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onehydrochloride of Example 27.

TABLE 9 Peak Angle d-Spacing Relative Intensity No. (2θ) [°] [Å] [%] 14.3 20.4 6.1 2 8.7 10.2 4.6 3 10.8 8.2 5.1 4 12.6 7.0 86.9 5 13.0 6.838.1 6 14.0 6.3 13.8 7 16.0 5.5 92.4 8 16.3 5.4 48.0 9 16.6 5.4 34.9 1017.1 5.2 13.2 11 19.3 4.6 13.4 12 19.7 4.5 44.1 13 20.2 4.4 77.1 14 21.74.1 19.3 15 23.4 3.8 100.0 16 24.3 3.7 71.1 17 24.9 3.6 41.2 18 26.5 3.431.7 19 27.3 3.3 15.7 20 28.3 3.2 12.5 21 30.6 2.9 7.8 22 32.3 2.8 19.223 33.0 2.7 14.1 24 34.2 2.6 7.9 25 36.8 2.4 4.2

Of the peaks shown in Table 9, the diffraction peak characteristic ofthe Form 1-type crystal of the present hydrochloride include peaks thatgive diffraction angles 2θ of 4.3°, 8.7°, 10.8°, 12.6°, 13.0°, 16.0°,17.1°, 19.3°, 19.7°, and 20.2°.

Table 10 shows a peak angle, d-spacing, and relative intensity thereofin the X-ray powder diffraction of the Form A-type crystal of6-(2-{4-[4-bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate of Example 28.

TABLE 10 Peak Angle d-Spacing Relative Intensity No. (2θ) [°] [Å] [%] 18.7 10.2 100.0 2 9.9 8.9 1.5 3 11.9 7.5 2.7 4 13.0 6.8 5.8 5 14.2 6.21.8 6 14.9 5.9 11.3 7 15.3 5.8 11.3 8 15.8 5.6 1.7 9 17.4 5.1 43.4 1017.7 5.0 6.3 11 18.2 4.9 6.5 12 18.5 4.8 4.5 13 19.3 4.6 7.9 14 19.9 4.55.1 15 20.4 4.4 12.5 16 21.6 4.1 7.2 17 21.8 4.1 5.2 18 22.1 4.0 8.0 1922.4 4.0 35.2 20 22.5 3.9 28.4 21 22.8 3.9 5.1 22 23.1 3.8 2.6 23 23.83.7 2.0 24 24.2 3.7 9.3 25 24.8 3.6 4.9 26 25.1 3.5 2.9 27 25.3 3.5 3.428 26.0 3.4 4.7 29 27.1 3.3 2.9 30 27.4 3.2 2.0 31 28.3 3.1 5.5 32 30.13.0 6.3 33 30.7 2.9 7.2 34 32.0 2.8 2.7 35 33.8 2.7 8.5 36 34.3 2.6 1.737 35.4 2.5 1.6 38 35.9 2.5 1.8 39 37.5 2.4 0.7 40 38.2 2.4 3.8 41 38.62.3 4.0 42 39.4 2.3 4.5 43 39.8 2.3 3.1 44 40.2 2.2 2.0 45 43.8 2.1 3.146 44.1 2.1 2.7 47 44.5 2.0 2.7 48 45.4 2.0 0.6 49 47.1 1.9 1.1 50 47.61.9 1.2 51 48.1 1.9 1.9 52 49.2 1.8 1.0 53 53.9 1.7 1.4

Of the peaks shown in Table 10, the diffraction peak characteristic ofthe Form A-type crystal of the present benzenesulfonate include peaksthat give diffraction angles 2θ of 8.7°, 11.9°, 13.0°, 14.9°, 15.3°,17.4°, 17.7°, 18.2°, 19.3°, and 20.4°.

Table 11 shows a peak angle, d-spacing, and relative intensity thereofin the X-ray powder diffraction of the Form B-type crystal of6-(2-{4-[4-bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate of Example 29.

TABLE 11 Peak Angle d-Spacing Relative Intensity No. (2θ) [°] [Å] [%] 18.9 10.0 100.0 2 10.0 8.8 7.3 3 11.2 7.9 3.0 4 12.0 7.4 3.4 5 12.5 7.15.3 6 13.3 6.7 1.2 7 14.0 6.3 7.6 8 14.4 6.1 2.7 9 15.3 5.8 18.2 10 16.95.3 12.1 11 17.0 5.2 15.3 12 17.6 5.0 76.0 13 17.9 5.0 8.2 14 18.9 4.712.1 15 19.4 4.6 5.3 16 20.1 4.4 5.4 17 20.6 4.3 12.6 18 21.0 4.2 2.0 1921.3 4.2 4.6 20 21.6 4.1 12.4 21 21.9 4.1 10.2 22 22.6 3.9 39.7 23 22.93.9 50.6 24 24.3 3.7 4.9 25 24.6 3.6 21.8 26 25.2 3.5 9.8 27 25.7 3.510.5 28 26.8 3.3 10.4 29 27.4 3.3 3.1 30 28.4 3.1 2.8 31 28.8 3.1 5.6 3229.1 3.1 5.3 33 29.3 3.0 7.7 34 30.8 2.9 1.7 35 31.4 2.8 5.2 36 33.1 2.76.5 37 34.3 2.6 11.3 38 36.0 2.5 11.9 39 36.7 2.4 3.0 40 37.4 2.4 6.1 4138.3 2.3 1.9 42 39.9 2.3 2.7 43 40.6 2.2 1.8 44 41.8 2.2 1.5 45 42.5 2.12.0 46 43.4 2.1 4.8 47 43.9 2.1 3.7 48 44.7 2.0 4.3 49 45.4 2.0 4.1 5046.3 2.0 4.1 51 46.8 1.9 1.9 52 48.1 1.9 1.4 53 49.7 1.8 1.7 54 51.0 1.81.1 55 54.0 1.7 1.3 56 54.6 1.7 1.3 57 57.3 1.6 0.5 58 59.6 1.6 1.6

Of the peaks shown in Table 11, the diffraction peak characteristic ofthe Form B-type crystal of the present benzenesulfonate include peaksthat give diffraction angles 2θ of 8.9°, 10.0°, 12.0°, 12.5°, 14.0°,16.9°, 17.0°, 17.6°, 18.9°, and 20.6°.

Table 12 shows a peak angle, d-spacing, and relative intensity thereofin the X-ray powder diffraction of the Form C-type crystal of6-(2-{4-[4-bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate of Example 30.

TABLE 12 Peak Angle d-Spacing Relative Intensity No. (2θ) [°] [Å] [%] 18.6 10.2 100.0 2 9.9 8.9 14.2 3 11.9 7.4 6.3 4 12.6 7.0 16.8 5 13.0 6.864.9 6 13.2 6.7 3.6 7 13.4 6.6 6.9 8 14.4 6.1 21.3 9 14.6 6.1 21.0 1014.9 6.0 4.0 11 15.9 5.6 0.7 12 17.4 5.1 2.7 13 17.8 5.0 6.7 14 18.0 4.963.8 15 18.4 4.8 20.4 16 18.5 4.8 14.7 17 19.0 4.7 4.0 18 19.3 4.6 9.019 19.6 4.5 45.2 20 19.8 4.5 34.4 21 21.2 4.2 14.3 22 21.3 4.2 17.5 2321.6 4.1 39.7 24 21.7 4.1 23.5 25 22.0 4.0 14.3 26 22.3 4.0 6.0 27 22.93.9 13.5 28 23.3 3.8 9.8 29 23.5 3.8 32.1 30 23.9 3.7 23.8 31 24.2 3.725.8 32 24.5 3.6 19.5 33 24.9 3.6 74.7 34 25.1 3.6 11.5 35 25.7 3.5 12.736 25.9 3.4 6.5 37 26.2 3.4 31.8 38 26.8 3.3 8.0 39 27.0 3.3 7.2 40 28.13.2 7.2 41 28.2 3.2 6.4 42 28.5 3.1 12.3 43 29.0 3.1 6.2 44 29.4 3.032.9 45 29.7 3.0 13.0 46 30.1 3.0 15.9 47 30.5 2.9 11.1 48 31.7 2.8 7.149 32.6 2.7 9.4 50 33.1 2.7 4.5 51 34.3 2.6 7.0 52 34.6 2.6 2.1 53 35.12.6 7.0 54 35.5 2.5 4.6 55 36.2 2.5 5.1 56 36.8 2.4 2.4 57 37.5 2.4 5.158 38.0 2.4 9.7 59 38.3 2.4 7.5 60 38.5 2.3 5.4 61 39.0 2.3 8.5 62 39.62.3 6.2 63 39.9 2.3 2.4 64 40.3 2.2 9.0 65 40.5 2.2 3.0 66 41.7 2.2 1.967 42.2 2.1 5.9 68 43.1 2.1 19.6 69 43.4 2.1 4.3 70 43.8 2.1 2.6 71 44.12.1 4.9 72 44.3 2.0 6.5 73 44.5 2.0 5.0 74 44.7 2.0 4.4 75 45.2 2.0 5.976 46.2 2.0 2.4 77 47.1 1.9 4.2 78 47.7 1.9 18.0 79 48.5 1.9 7.2 80 48.81.9 3.1 81 50.1 1.8 1.3 82 50.9 1.8 1.9 83 53.6 1.7 1.5 84 54.4 1.7 2.485 57.1 1.6 2.3 86 58.5 1.6 3.8 87 58.9 1.6 0.9 88 62.9 1.5 0.6 89 63.51.5 3.2

Of the peaks shown in Table 12, the diffraction peak characteristic ofthe Form C-type crystal of the present benzenesulfonate include peaksthat give diffraction angles 2θ of 8.6°, 9.9°, 12.6°, 13.0°, 14.4°,14.6°, 18.0°, 18.4°, 19.6°, and 19.8°.

Table 13 shows a peak angle, d-spacing, and relative intensity thereofin the X-ray powder diffraction of the Form A-type crystal of6-(2-{4-[4-bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onemonofumarate of Example 31.

TABLE 13 Peak Angle d-Spacing Relative Intensity No. (2θ) [°] [Å] [%] 17.6 11.6 26.5 2 10.0 8.9 53.6 3 11.5 7.7 30.4 4 11.8 7.5 52.5 5 12.8 6.915.8 6 13.4 6.6 32.4 7 13.7 6.5 51.5 8 14.1 6.3 17.1 9 14.6 6.0 29.2 1015.3 5.8 35.3 11 16.0 5.5 24.1 12 16.8 5.3 46.3 13 17.1 5.2 28.5 14 17.45.1 53.7 15 18.3 4.8 89.4 16 19.4 4.6 67.9 17 19.6 4.5 69.4 18 20.2 4.440.7 19 20.9 4.3 75.3 20 21.3 4.2 43.4 21 22.0 4.0 40.8 22 22.6 3.9 71.123 23.2 3.8 100.0 24 23.8 3.7 26.4 25 24.9 3.6 62.8 26 25.2 3.5 37.0 2725.7 3.5 98.0 28 26.5 3.4 16.5 29 28.2 3.2 18.4 30 30.3 2.9 17.9 31 34.12.6 7.9

Of the peaks shown in Table 13, the diffraction peak characteristic ofthe Form A-type crystal of the present fumarate include peaks that givediffraction angles 2θ of 7.6°, 10.0°, 11.5°, 11.8°, 14.6°, 15.3°, 16.0°,17.4°, 18.3°, 19.6°, 20.9°, 22.0°, and 23.2°.

Table 14 shows a peak angle, d-spacing, and relative intensity thereofin the X-ray powder diffraction of the Form A+-type crystal of6-(2-{4-[4-bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onemonofumarate of Example 32.

TABLE 14 Peak Angle d-Spacing Relative Intensity No. (2θ) [°] [Å] [%] 17.4 12.0 1.4 2 10.1 8.8 2.4 3 11.1 8.0 5.9 4 12.8 6.9 2.4 5 13.8 6.4 1.06 14.7 6.0 17.1 7 16.0 5.5 5.6 8 17.1 5.2 1.1 9 17.6 5.0 1.8 10 18.4 4.884.7 11 19.5 4.6 7.1 12 19.8 4.5 11.1 13 21.2 4.2 1.5 14 22.2 4.0 23.015 23.4 3.8 8.0 16 25.1 3.5 3.5 17 25.9 3.4 100.0 18 26.7 3.3 7.5 1928.7 3.1 1.6 20 29.7 3.0 2.7 21 30.3 2.9 7.2 22 33.0 2.7 1.2 23 33.5 2.76.4 24 34.4 2.6 2.5 25 35.9 2.5 1.3 26 38.2 2.4 2.2 27 39.5 2.3 1.6 2843.2 2.1 4.0 29 49.3 1.8 3.7 30 53.3 1.7 4.4

Of the peaks shown in Table 14, the diffraction peak characteristic ofthe Form A+-type crystal of the present fumarate include peaks that givediffraction angles 2θ of 7.4°, 10.1°, 11.1°, 14.7°, 16.0°, 18.4°, 19.8°,22.2°, 23.4°, 25.9°, and 26.7°.

Preparation Example 1 Production of Tablets

6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-1H-inden-1-one(5 g), lactose (80 g), corn starch (30 g), crystalline cellulose (25 g),hydroxypropylcellulose (3 g), light anhydrous silicic acid (0.7 g), andmagnesium stearate (1.3 g) are mixed and granulated by a standard methodand compressed into 1000 tablets of 145 mg each.

Preparation Example 2 Production of Powders

6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate (10 g), lactose (960 g), hydroxypropylcellulose (25 g),and light anhydrous silicic acid (5 g) are mixed by a standard methodand then prepared into powders.

INDUSTRIAL APPLICABILITY

A benzylpiperidine compound of the present invention represented by theformula (1) and a pharmaceutically acceptable salt thereof arecharacterized in terms of a chemical structure by having adi-substituted benzyl group having a 2-methoxyethoxy or 2-hydroxyethoxygroup at 3-position of the benzene ring moiety and having, at 1-positionof piperidine, a phenylethyl group of which the benzene ring moietyfused with a saturated ring comprising an oxo group. Thebenzylpiperidine compound of the present invention or thepharmaceutically acceptable salt thereof is a novel serotonin reuptakeinhibitor that has an improved human serotonin reuptake inhibitoryeffect in combination with affinity for human serotonin 1A receptors,has a weaker inhibitory effect on CYP2D6, one of the molecular speciesof human cytochrome P450, and undergoes small CYP2D6 contribution todrug metabolism in humans. Therefore, it can be used as, for example, ahighly safe therapeutic or preventive drug excellent in therapeuticeffect on diseases such as depression and anxiety (anxiety disorder).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction pattern of a Form 1-type crystalof6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onehydrochloride of Example 27 obtained in X-ray powder diffractionanalysis of Test Example 6;

FIG. 2 is an X-ray powder diffraction pattern of a Form A-type crystalof6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate of Example 28 obtained in X-ray powder diffractionanalysis of Test Example 6;

FIG. 3 is an X-ray powder diffraction pattern of a Form B-type crystalof6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate of Example 29 obtained in X-ray powder diffractionanalysis of Test Example 6;

FIG. 4 is an X-ray powder diffraction pattern of a Form C-type crystalof6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onebenzenesulfonate of Example 30 obtained in X-ray powder diffractionanalysis of Test Example 6;

FIG. 5 is an X-ray powder diffraction pattern of a Form A-type crystalof6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onemonofumarate of Example 31 obtained in X-ray powder diffraction analysisof Test Example 6; and

FIG. 6 is an X-ray powder diffraction pattern of a Form A+-type crystalof6-(2-{4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidin-1-yl}ethyl)-2,3-dihydro-4H-chromen-4-onemonofumarate of Example 32 obtained in X-ray powder diffraction analysisof Test Example 6.

1. A compound represented by the formula (12) or a pharmaceuticallyacceptable salt thereof:

wherein X represents a methylene group or an oxygen atom; n representsan integer of 1 to 3; and LG¹ represents an iodine atom, a bromine atom,a chlorine atom, or a substituted sulfonyloxy group.
 2. The compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof,wherein LG¹ represents a bromine atom, or a substituted sulfonyloxygroup.
 3. The compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, wherein LG¹ represents a benzenesulfonyloxygroup, or a p-toluenesulfonyloxy group.
 4. The compound according toclaim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound represented by the formula (12) is selected from the groupconsisting of the following compounds:(2-(4-Oxo-3,4-dihydro-2H-chromen-6-yl)ethyl 4-methylbenzenesulfonate,2-(8-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl)ethyl4-methylbenzenesulfonate, 2-(3-Oxo-2,3-dihydro-1H-inden-5-yl)ethyl4-methylbenzenesulfonate,2-(5-Oxo-2,3,4,5-tetrahydro-1-benzoxepin-7-yl)ethyl4-methylbenzenesulfonate, and(2-(4-Oxo-3,4-dihydro-2H-chromen-6-yl)ethyl benzenesulfonate).
 5. Thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound represented by the formula (12) isselected from the group consisting of the following compounds:(2-(4-Oxo-3,4-dihydro-2H-chromen-6-yl)ethyl 4-methylbenzenesulfonate,and (2-(4-Oxo-3,4-dihydro-2H-chromen-6-yl)ethyl benzenesulfonate).